+1 Recommend
1 collections

      Interested in becoming an AMM published author?

      • Platinum Open Access with no APCs.
      • Fast peer review/Fast publication online after article acceptance.

      Check out the call for papers on our website https://amm-journal.org/index.php/2023/04/26/acta-materia-medica-call-for-papers-2/

      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      PROTAC technology for the treatment of Alzheimer’s disease: advances and perspectives



            Neurodegenerative diseases are characterized by the progression of neuronal degeneration, resulting in dysfunction of cognition and mobility. Many neurodegenerative diseases are due to proteinopathies arising from unusual protein accumulation and aggregation. The aggregation of misfolded proteins, such as β-amyloid, α-synuclein, tau, and polyglutamates, is a hallmark of Alzheimer’s disease (AD). These aggregated proteins are undruggable targets and usually do not respond to conventional small-molecule agents. Therefore, developing novel technologies and strategies for decreasing the levels of protein aggregates is critical for the treatment of AD. Recently, the emerging proteolysis targeting chimera (PROTAC) technology has been considered for artificial, selective degradation of aberrant target proteins. These engineered bifunctional molecules engage target proteins, which are then degraded either by the cellular degradation machinery via the ubiquitin-proteasome system or through the autophagy-lysosome degradation pathway. Although PROTAC technology is preferable to oligonucleotides and antibodies for the treatment of neurodegenerative diseases, many limitations, such as their pharmacokinetic properties, tissue distribution, and cell permeability, must be addressed. Herein, we review recent advances in PROTAC technology, as well as PROTACs’ limitations, for the pharmaceutical targeting of aberrant proteins involved in AD. We also review the therapeutic potential of dysregulated signaling, such as the PI3K/AKT/mTOR axis, for the management of AD.

            Main article text

            1. INTRODUCTION

            Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the leading cause of dementia in older people and the sixth leading cause of death [1]. In 2020, 6.2 million Americans 65 years of age or older were living with AD [1]. Early-onset AD due to inherited genetic mutations, such as those in APP, APOE4, and PS1, has also been reported among people under the age of 65 and affects approximately 200,000 Americans [2]. The earliest symptom is remembering new events, whereas more advanced symptoms include linguistic difficulties, mood swings, confusion, lack of motivation, self-neglect, and behavioral problems [3]. The pathogenesis of AD is not fully understood, and importantly is irreversible in late stages, such as those involving brain atrophy; therefore early AD diagnosis and treatment remain unmet needs.

            Two pathological, aberrant structures in damaged neuronal cells have been identified as the main pathological hallmarks of AD: senile plaques and neurofibrillary tangles (NFT) [4]. Senile plaques are usually caused by the aberrant deposition of aggregated protein fragments called β-amyloid (Aβ; specifically Aβ42 and Aβ40) among nerve cells [5]. In this event, called amyloidosis of the brain, Aβ peptides are cleaved from the amyloid precursor protein (APP) and aggregate as soluble toxic oligomeric Aβ. The aggregation of these soluble toxic oligomers results in the creation of hydrophobic surfaces; subsequently, insoluble fibrils are formed for disruption of the phospholipid bilayer [6], which is considered the main underlying cause of AD [7]. NFT are constructed from abnormal fibers of hyperphosphorylated tau protein inside neuronal cells [8]. Notably, hyperphosphorylation of tau results in the formation of tangles that eventually damage the structure and function of neuronal cells, and are considered another major pathological feature of AD [9]. In fact, the mechanistic principle underlying the formation of both senile plaques and NFT has been well established and is considered a key hallmark of AD [10, 11] ( Figure 1 ).

            Figure 1 |

            Therapeutic targets in Alzheimer’s disease signaling.

            The formation of NFT and senile plaques in AD signaling introduces several therapeutic targets. Four genes are mainly involved in AD pathogenesis: amyloid precursor protein (APP), apolipoprotein E (ApoE), presenilin 1 (PSEN1), and presenilin2 (PSEN2). Increased levels of Aβ peptides are caused by mutations in APP and PSEN, thus leading to the formation of Aβ42, the main component of senile plaques. Cleavage of APP by either alpha-secretase or beta-secretase initiates extracellular release of soluble APP peptides, sAPPα, and sAPPβ, and retains the corresponding membrane-anchored C-terminal fragments, C83 and C99. Alternatively, PSEN1/Nicastrin (NCSTN)-mediated gamma-secretase processing of C99 releases the Aβ proteins Aβ40/42. In neuronal cell bodies, neurite outgrowth is stimulated by ApoE-containing lipoprotein lipase (LPL) via binding interactions between LRP and APP, thus resulting in the production of proteolytic fragments (Aβ) [161]. The accumulation of Aβ results in blocked ion channels, mitochondrial oxidative stress, activation of TNFR-regulated caspase 8, and ultimately neuronal cell death. However, GSK-3 phosphorylates tau at several sites, thus resulting in partial inhibition of tau’s biological activity in AD [162]. Under abnormal Ca2+ homeostasis, the stimulation of calpain mediates the cleavage of p35 to p25, thus activating CDK5 and leading to tau hyperphosphorylation and APP truncation [163]. Finally, the elevated Ca2+ stimulates neuronal NO synthase, thereby leading to the production of nitrogen species and reactive oxygen species [164]. SNCA: α-synuclein; PEN2: presenilin enhancer (gamma-secretase subunit); APH1A: Aph-1 homolog a (gamma-secretase subunit); TNFR: tumor necrosis factor receptors; FADD: Fas-associated protein with death domain; CASP8: caspase 8; nNOS: neuronal nitric oxide synthase.


            Normal cells undergo a self-controlling processes enabling homeostasis by preventing prolonged damage in response to environmental conditions. Several neurodegenerative diseases are caused by misfolded proteins that aggregate into β-sheet structures [6]. Cells are usually equipped with defense machinery against misfolded and aggregated proteins, which allows them to preserve homeostasis through two main strategies: (a) misfolded proteins are refolded with a plethora of molecular chaperones, and (b) if refolding is not possible, cells eliminate the aggregated proteins and consequently avoid neurodegenerative diseases. Loss of these defensive machineries increases the deposition of protein aggregates and results in the development of neurodegenerative diseases. Below, we introduce the ubiquitin-proteasome system (UPS) and autophagy pathways, which are the main defensive machineries for protein quality control in neuronal cells.

            2.1 The ubiquitin-proteasome system

            The UPS is essential for protein homeostasis through quality control in cells [12]. Ubiquitination results in the degradation of “unwanted” proteins via the 26S proteasome. In this process, ubiquitin, a 76-amino-acid protein, is used for monoubiquitylation and/or polyubiquitination through its covalent attachment to a target protein. Ubiquitination occurs through a multistep, reversible enzymatic cascade including E1, E2, and E3 enzymes [13]. The eight amino group of N-terminus or Lysine residue (K6, K11, K27, K29, K33, K48, K63, and M1) of the ubiquitin protein provide different “ubiquitination” signals [14] with diverse functional consequences ( Figure 2 ).

            Figure 2 |

            Schematic representation of E3 ligase biology.

            The ubiquitination of cellular proteins is triggered by the E1 enzyme, which utilizes the formation of Ub-AMP. After this catalytic reaction, ubiquitin is transferred to an E2 enzyme, and the thioester-linked E2-Ub complex is activated. Finally, an E3 ligase enzyme transfers the ubiquitinated protein from the E2 enzyme to a target protein. The ubiquitination process can be reversed by deubiquitinating enzymes (DUBs), which catalyze the cleavage of ubiquitin from target proteins or substrates. E1, ubiquitin-activating enzymes; E2, ubiquitin-conjugating enzymes; E3, ubiquitin ligases; Ub, ubiquitin.

            Protein turnover is essential for synaptic plasticity and memory in the nervous system, and should be considered in the regulation of protein stability and function in neuronal cells [15]. The UPS controls most protein functions in the postsynaptic response in neuronal cells. Meanwhile, protein aggregates are largely due to a decrease in degradation rather than an increase in synthesis [16]. Therefore, neurons fail to clear abnormal proteins in neurodegenerative proteinopathies. Understanding the UPS in each neuron is necessary for developing novel therapeutic approaches by enhancing proteasomal degradation for removing pathogenic aggregates in neuronal cells.

            2.2 Autophagy

            Autophagy, another important system, is a conserved degradation process supporting protein homeostasis in eukaryotic cells. Autophagy mainly processes larger cytosolic structures such as cellular protein aggregates and organelles within lysosomes [17]. The best-known form of autophagy is macro-autophagy, in which protein targets are sequestered in the phagophore, a cytosolic membrane compartment [18]. Mechanistically, cellular targets are engulfed by autophagosomes, which are transported via the cytoskeleton and subsequently fuse with lysosomes. This mechanism expedites the degradation of cytoplasmic substrates such as misfolded proteins (aggrephagy), highly loaded peroxisomes (perophagy), abnormal mitochondria (mitophagy), and pathogenic organisms (xenophagy) [19]. In fact, several intracellular proteins, known as autophagy-related proteins, govern autophagy processes [20] ( Figure 3 ).

            Figure 3 |

            Protein degradation pathways in neuronal cells along with targeted protein degradation strategies.

            PROTAC, proteolysis-targeting chimera; AUTAC, autophagy-targeting chimera; ATTEC, autophagosome-tethering compound; LYTAC, lysosome-targeting chimera; CI-M6PR, cation-independent mannose 6-phosphate receptor; LC3, microtubule-associated proteins 1A/1B light chain 3B; Ub, ubiquitin; E3, ubiquitin ligase; POI, protein of interest.

            Regarding the protective function of autophagy in neuronal physiology, the accumulation of abnormal tau proteins might be due to impaired autophagy within neurons [21]. Greater activation of autophagy increases degradation of the tau protein and decreases intracellular tau aggregation [22]. In addition, increased activity of autophagy effectively decreases the Aβ content, particularly in early stages of Aβ accumulation [23, 24]. Concordantly, Aβ has been found to arise from amyloid precursor protein within autophagosomes, thus indicating a unique link between the autophagy pathway and the formation of Aβ plaques [25].


            Strategies of targeted protein degradation have recently emerged as modalities in drug discovery, wherein bifunctional small molecules hijack the cellular degradation machinery and direct protein targets for ubiquitin-mediated degradation. In 2001, the Crews group developed the first peptide-based bifunctional molecules, including the ligands of a target protein and a ubiquitin E3, and used them to construct proteolysis-targeting chimeras (PROTACs). This technology has since shown promise for the regulation of key target proteins that are otherwise untargetable. Several methods based on chemically mediated targeted protein degradation have been established, including hydrophobic tagging, molecular glues, autophagy-targeting chimeras, autophagosome-tethering compounds (ATTECs), lysosome-targeting chimeras (LYTACs), and PROTACs ( Figure 3 ).

            In the hydrophobic-tagging experimental system, the addition of hydrophobic tags (e.g., Boc3Arg or adamantyl) to ligands induces structural changes and the formation of hydrophobic patches that initiate the unfolding of protein targets, which are subsequently degraded via the protein-homeostasis machinery [26]. In the molecular-glue strategy, degraders such as lenalidomide interact with the target protein and hijack a specific ubiquitin ligase, thus resulting in initiation of ubiquitination and subsequent target-protein degradation by the 26S proteasome [27].

            Moreover, Takahashi et al. have recently developed a novel targeted-clearance strategy termed autophagy-targeting chimeras (AUTACs), which are bifunctional molecules conjugated by small molecules that induce autophagy [28]. In brief, S-guanylation (with guanine derivatives) is used to tag chimeric molecules (including the guanine component and a specific ligand for a desired protein target) to selectively direct protein substrates to the autophagy system for programmed destruction. AUTACs result in the removal of fragmented mitochondria and the biogenesis of normal mitochondria. Thus, AUTACs might provide a modality for developing autophagy-based drugs with specific targets to combat AD. In addition, other strategies using autophagy for targeted protein degradation have been reported, including ATTECs and LYTACs [29]. In brief, ATTEC molecules bind the target protein along with LC3, protein that recruits target proteins to autophagosomes for degradation via autophagy. LYTACs are heterobifunctional molecules that target extracellular and membrane-associated proteins by conjugation, and engage endosomes and lysosomes through the recruitment of protein targets to the lysosome-shuttling receptor at the cell surface [29].

            4. PROTACS

            PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the powerful cellular degradation systems [3032]. PROTACs recruit target proteins to an E3 ubiquitin ligase (usually MDM2, Von Hippel Lindau (VHL), IAPs, and CRBN ligases) via an optimal linker ( Figure 4 ). The formation of a complex between the protein of interest (POI) and the E3 ligases triggers POI ubiquitination and subsequent degradation by the 26S proteasome in eukaryotic cells [3338] ( Figure 5 ). The first PROTAC degrader was developed to target the androgen receptor for the treatment of metastatic castration-resistant prostate cancer [39, 40]. After validation of the proof of concept, the use and development of PROTAC technology markedly increased in industrial and academic settings. This broad adoption is mainly because PROTACs: 1) can block both enzymatic and non-enzymatic functions of proteins, 2) can destroy “undruggable” POIs, 3) have high specificity and selectivity, 4) can rapidly and reversibly eliminate protein targets, and 5) have promise in overcoming drug resistance [41]. Drug resistance is a major problem in anticancer therapy, and PROTAC technology is expected to generate more effective drugs to circumvent drug resistance. The use of PROTACs should be highly beneficial because of its novel mechanism of action for decreasing target-protein levels with lower drug doses than conventionally used. The first oral PROTACs assessed in clinical trials were ARV-110 for prostate cancer and ARV-471 for breast cancer, both from Arvinas [42]. In brief, PROTAC molecules can be used to cure autoimmune and inflammatory conditions, and treat diseases such allergies, asthma, cardiovascular disease, and AD [43].

            Figure 4 |

            E3 ligase ligands commonly used for PROTACs.

            Derivatives of thalidomide targeting Cereblon (CRBN) and the ligand of Von Hippel Lindau (VHL) are shown. The asterisk shows the point of attachment to the linker.

            Figure 5 |

            Schematic illustration of PROTAC mechanisms of action.

            (A) The E1 Ubiquitin-activating enzyme initiates transfer of Ubiquitin (Ub) to a target protein through the E1-E2-E3 enzymatic cascade. Then, the ubiquitinated target protein is degraded by the 26S proteasome. (B) Without PROTACs, the target protein is not recruited for ubiquitination. The PROTAC molecule attaches to a POI and the E3 ubiquitin ligase, thus resulting in ubiquitination and subsequent proteasomal degradation.


            Here, we introduce several PROTACs developed for the elimination of misfolded proteins, which are a major cause of neurodegenerative diseases. PROTACs provide excellent therapeutic benefits in targeting pathogenic proteins for degradation. We introduce the major dysregulated proteins, including tau and α-synuclein (αSyn), that cause neurodegenerative diseases such as AD. We will discuss the major aberrant protein/signaling pathways, contributing to AD, including the hypoxia/HIF1α, phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/AKT, glycogen synthase kinase 3β (GSK-3β), and bromodomain and extra-terminal domain (BET) pathways.

            5.1 The main pathological targets in Alzheimer’s disease
            5.1.1 Tau

            The tau proteins are abundant in neuronal cells, where they stabilize microtubules in axons; consequently, they are is known as microtubule-associated proteins for axonal transport [4448]. Increased aggregation of tau protein is correlated with synaptic dysfunction, thus leading to abnormal localization of tau from axons to the somatodendritic region. NFT are aggregations of tau protein in neuronal cells in AD [44]. Hyperphosphorylated tau proteins aggregate and form NFT. Tauopathies, characterized by the development of neurofibrils from the hyperphosphorylation of tau, can arise in atypical Parkinson syndromes [49]. Dysregulation of tau is also an important issue in frontotemporal dementia and in Aβ toxicity. Thus, tau has been suggested as an attractive target for the potential treatment of AD.

            In 2016 and 2018, Chu and Lu et al. reported that peptide forms of PROTACs can degrade tau proteins [50, 51]. Interestingly, the peptidic PROTAC TH006 degrades tau in the CA3 region of the hippocampus in vivo ( Table 1 ). Later, in 2019, Silva et al. constructed a set of unique PROTACs by using a tau PET tracer as a warhead [52] for targeting tau in human differentiated frontotemporal dementia (FTD) neurons. PROTAC T807 treatment sufficiently degraded the wild-type (WT) protein and the tau variants A152T and P301L in neurons, with K d values of 1.8, 2.1, and 1.7 μM, respectively. The authors also established a second PROTAC, QC-01-175, that specifically degrades tau variants in neurons with FTD rather than healthy neurons ( Figure 6 and Table 1 ). In addition, QC-01-175 rescues stress vulnerability in patient-derived neuronal cell models of FTD.

            Table 1 |

            Properties of PROTACs with peptide-mediated or chemical-mediated targeting

            PROTACEntityc Tau recognizedLinkerRecruiting E3 ligasea Cell- penetrating peptideIC50 (μM) K d value (μM) In vivo studyPK studyPMID
            Peptide- mediated targetingTH006YQQYQDATADEQGGSGSALAPYIP (VHL)RRRRRRRRa None0.3944 ± 0.1589Tau degradation in the CA3 region of the hippocampusNot reported27105281
            Peptide 1YQQYQDATADEQGGSGSLDPETGEYL (Keap1)RRRRRRRRNoneNot reportedNot reportedNot reported29407955
            Chemical-mediated targetingQC-01-175WTb CRL4CRBN 8.5591.2 ± 0.44Not reportedNot reported30907729
            A152Tb 1.7 ± 0.54
            P301Lb 2.5 ± 1.31
            T807WTCRL4CRBN 0.1441.8 ± 0.99Not reportedNot reported30907729
            A152T2.1 ± 0.50
            P301L1.7 ± 0.77
            C004019Total, pS214, and pS404 tauVHL0.00785Not reportedRobust tau clearance in the hippocampus and cortex; improvement in synaptic and cognitive functionTmax (h) = 0167; Cmax (ng/ml) = 10.8; AUClast (h×ng/ml) = 8.4233859747

            aRepresents poly-D-arginine.

            bRepresents human recombinant biotinylated-tau WT, A152T, and P301L, respectively.

            cThe name and identification of drugs.

            Tmax: time point at which the drug concentration was highest; Cmax: maximum drug concentration; AUClast: area under the curve (the integral from the beginning to the last point in time).

            Figure 6 |

            Chemical structure of tau-targeting PROTACs: QC-01-175 and C004019.

            In 2021, Wang et al. developed a PROTAC using a linker connecting tau to a VHL ligand [53] ( Figure 6 ). In in vitro and in vivo experiments, their PROTAC, C004019, cleared tau protein under both physiological and pathological conditions. Interestingly, a single dose or infrequent administration of the PROTAC (once per 6 days) resulted in a sustained tau decrease and alleviated Aβ-induced neurotoxicity in the brain in a 3×Tg-AD mouse model, without causing clear abnormalities. Robust tau clearance in the hippocampus and cortex in mice was observed, along with improvements in synaptic and cognitive function. These findings indicate that this PROTAC is an efficient drug candidate for tauopathies and the treatment of AD ( Table 1 ).

            5.1.2 α-Synuclein

            The amino acid sequence of αSyn includes three distinct domains: the N terminus, the C terminus, and a central hydrophobic region through which α-synuclein assembles into amyloid fibrils [54]. Misfolded and aggregated αSyn expands in a prion-like fashion among cells, thus resulting in fibril amplification and progression to synucleopathies [55]. Because the deposition of αSyn is initiated in the enteric nervous system, the pathogenesis of synucleopathies is assumed to begin in enteric nerves before deposition in the brain. In fact, patients with Parkinson’s disease (PD) experience gastrointestinal problems before motor deficits [56]. The symptoms of PD and AD are moderately similar, but AD pathologically affects the cerebral cortex and hippocampus, whereas PD occurs mainly in the substantia nigra [57]. Although patients with AD show PD symptoms, and vice versa, patients with PD show clearer cognitive dysfunction; these findings suggest a pathological synergy between Aβ and αSyn. Studies have revealed that αSyn is highly expressed in brain regions with abundant AD lesions, and the enrichment of αSyn in the cortical region is correlated with the presence of Aβ [58].

            Recently, Kargbo et al. have developed a bifunctional PROTAC compound that targets αSyn protein [59]. Their compound was developed by using a VHL moiety to target POIs. The linker places the VHL E3 ubiquitin ligase in proximity to target proteins for UPS degradation. The representative PROTAC has been found to prevent the accumulation and aberrant aggregation of αSyn protein in HEK293 cells stably expressing TREX αSyn A53T [59].

            5.2 Aberrant target proteins dysregulated in the AD microenvironment
            5.2.1 Hypoxia/HIF1α signaling

            Insufficient amounts of oxygen, a condition known as hypoxia, affect the pathological and physiological function of cells [60]. Under hypoxia, prolyl hydroxylases, major molecular sensors of oxygen, cannot catalyze prolyl hydroxylation of hypoxia-induced factor alpha (HIF1α) and AKT [61, 62]. Hydroxylated HIF1α is recognized and polyubiquitinated by the E3 ligase VHL, thus resulting in HIF1α degradation by the UPS [63, 64]. Hypoxia and/or HIF1α accumulation in VHL-deficient cells results in the recruitment of HIF1β and the transcriptional regulation of numerous genes [64]. Phosphorylation of histone H2AX plays an important role in the maintenance and inhibition of HIF1α degradation under hypoxia [65, 66].

            Decreased oxygen in the brain is also associated with neurodegenerative diseases such as AD. In fact, the central nervous system (CNS) is highly sensitive to the oxygen supply, such as during aging, in which delivery of oxygen via the cardiovascular system is diminished [67]. Hypoxia also supports the formation of plaques and consequently leads to memory deficits in a mouse model for AD [68]. In the brain under hypoxia-driven AD, several molecular signaling pathways are also activated, thereby supporting oxidative stress [69], AKT/mTOR activation [70], angiogenesis [71], and metabolic activation [72]. Hypoxia rapidly induces the expression of Aβ, cyclooxygenase-2 (COX-2), and presenilin 1 (PS1), thereby resulting in neuroinflammation in the brain in AD [73]. However, under extended hypoxic conditions, Ca2+ channels are upregulated, thus supporting the production of Aβ [74]. Importantly, HIF1α triggers transcriptional expression of VEGF [75] and BACE1 (a major biomarker of AD) [76], and consequently increases Aβ deposition and neurotic plaque production in a transgenic mouse model [76]. HIF1α therefore induces tau phosphorylation partly through the regulation of several signaling pathways, including the GSK3β, cyclin-dependent kinase 5 (CDK5), and mTOR pathways [77, 78]. Moreover, Glut1 and Glut3, other HIF1α-target genes and major brain glucose transporters, show diminished expression in AD [79].

            In early 2004, Schneekloth et al. reported that peptide-based PROTACs recognize the transcription of HIF1α and bind VHL [80]. The authors added a poly D-arginine tag to the peptide sequence to facilitate cell penetration. Interestingly, the discovery of a small molecule inhibiting the interaction between HIF1α and VHL led to the establishment of several PROTACs linking VHL to other target POIs with high specificity and affinity [81, 82]. Aging can induce hypoxia/HIF1α, thus resulting in the dysregulation of several molecular signaling pathways in neurons and subsequent AD pathogenesis; these aspects should be considered for careful selective degradation with novel PROTAC technology.

            5.2.2 PI3K/mTOR signaling

            PI3K, a member of the PI3K/AKT/mTOR signaling pathway, functions as a phosphatidylinositol kinase. It primarily regulates apoptosis, proliferation, and differentiation of cells, and its overexpression drives tumorigenesis. Moreover, mTOR responds to a wide range of extracellular stimuli in the regulation of cell growth and metabolic homeostasis [83]. The mTOR pathway also regulates several diseases, including cancer [84], diabetes [85], and neurodegenerative pathological conditions [86]. In fact, inhibiting mTOR increases the lifespan of several organisms, such as C. elegans [87] and mice [88], whereas rapamycin, an mTOR-specific inhibitor, extends their lifespan [8993]. Importantly, mTOR kinase promotes tau phosphorylation by regulating multiple kinases, including GSK3, protein kinase A, and CDK5 [94]. Moreover, mTOR directly phosphorylates and inhibits protein phosphatase 2A, a major phosphatase downregulated in the AD brain [95], thus increasing tau phosphorylation [96]. Furthermore, downstream targets of mTOR, such as S6K and eukaryotic translation factor 4E, increase the mRNA translation of Tau, thereby indicating that overactivation of mTOR results in accumulation of tau protein [97]. Unexpectedly, the administration of Aβ in the hippocampus in normal mice has been found to activate the mTOR pathway; these findings demonstrate the role of amyloid precursor in the activity of mTOR signaling [98]. Furthermore, rapamycin decreases cognitive deficits in tau pathology through amelioration of Aβ in the brains of mice with AD [99]. Thus, mTOR disrupts tau homeostasis and results in the aggregation of tau and the formation of NFT in AD pathogenesis. These findings suggest a potential strategy for the treatment of AD through targeting mTOR.

            Recently, several PI3K inhibitors have been established, most of which have limitations because of inadequate selectivity and adverse effects [100, 101]. Consequently, the improvement of unique PI3K-targeting PROTACs has been recognized as a powerful strategy. In 2018, Jiang et al. established a set of prospective PI3K degraders using lenalidomide in the link with ZSTK474 inhibitors [102]. Although this PROTAC revealed lower enzymatic activity than ZSTK474, it successfully degraded PI3K at 10 μM, and decreased the phosphorylation of GSK-3β, S6K, and AKT in the PI3K/AKT/mTOR signaling pathway.

            5.2.3 AKT

            AKT, a central member of the PI3K/AKT/mTOR signaling pathway, is a serine/threonine kinase that regulates several cellular processes such as survival, proliferation, and metabolism. Some gain-of-function mutations and/or the activation of oncogenes such as PI3K and receptor tyrosine kinases, and/or the loss of the tumor suppressor function of PTEN, can lead to hyper activation of AKT in the cancer progression [103]. Moreover, GSK3β-mediated tau phosphorylation is critical for the initiation of AKT-sulfhydration [104]. Therefore, AKT is considered to be central to PI3K/AKT/mTOR signaling and should be an interesting therapeutic target to combat AD.

            In 2019, You et al. developed a specific small-molecule degrader based on the conjugation of a CRBN ligand with GDC-0068 as an AKT inhibitor [105]. This engineered PROTAC has been found to inhibit AKT1, AKT2, and AKT3 with IC50 values of 2.0 nM, 6.8 nM, and 3.5 nM, respectively, in contrast to GDC-0068’s IC50 values of 5 nM, 18 nM, and 8 nM, respectively. In addition, this PROTAC destabilizes all three isoforms and decreases AKT-downstream signaling. The engineered PROTAC also downregulates cell proliferation much more efficiently than its parental inhibitor and therefore should be valuable for targeted degradation of AKT.

            5.2.4 GSK-3β

            GSK-3 is a serine/threonine protein kinase and a member of the phosphotransferase family [106]. Pathologically, GSK-3β regulates several process through tau phosphorylation and also results in the production of Aβ peptide, thus causing NFT and amyloid plaques in AD [104]. Moreover, the proinflammatory function of GSK-3β causes neuronal loss [107109] and neurodegenerative disease [110]; therefore, this kinase should be considered therapeutic target for AD treatment [111113]. In 2021, Jiang et al. reported the first set of GSK-3β-targeting PROTACs, developed by using CRBN as an E3 ubiquitin ligase [114]. Their PROTAC efficiently induces degradation of GSK-3β protein (44%) with an IC50 value of 2.8 μM; this PROTAC should therefore be considered as an effective GSK-3β degrader.

            5.2.5 BET

            Dysregulation of inflammation, a critical process in the pathology of many CNS diseases, occurs through several pathways, including NF-kB and Nrf2 signaling in inflammation. BET proteins include four members (BRD2, BRD3, BRD4, and BRDT) that play critical roles in the transcriptional regulation of the inflammatory response [115, 116]. For example, BETs assemble the histone-acetylation-dependent chromatin complex for the expression of inflammatory genes. Early studies have also shown that BET inhibition activates anti-inflammatory pathways; therefore, BRD2, BRD3, and BRD4 proteins may play critical roles in AD and other neuroinflammatory disorders. [116120]. Targeting BET proteins with a small-molecule inhibitor (JQ1) has been found to downregulate several proinflammatory regulators, such as IL-1β and TNF-α, and to be followed by tau phosphorylation at Ser396 in the frontal cortex and the hippocampus in the 3×Tg mouse model of AD [121]; however, these mice do not show memory deficits and amelioration of learning. In the APP/PS1 AD mouse model, JQ1 enhances long-term potentiation (LTP) and cognitive function [122]. Moreover, JQ1 activates the expression of hippocampal genes responsible for the activation of ion channels and DNA repair [122]. Chemical probes such as pan-BETi(s) serve as ideal PROTACs for targeting BET proteins, owing to their potential for BET identification and recruitment.

            The first PROTAC-targeted BET proteins (dBET1) were identified in 2015 and included an E3 ligase and a BRD4 BD binding moiety (JQ1 or OTX015) [123]. The BET PROTACs have been shown to identify and recruit the CRBN E3 ubiquitin ligase for efficient and selective degradation of BRD4 protein in vitro and in vivo [123127]. Moreover, a proteomic study has indicated that dBET1 decreases BET proteins by 8- to 10-fold, along with several other BET-target proteins [123].


            6.1 Advantages

            PROTAC technology is favorable for the treatment of CNS diseases because it has several advantages over traditional approaches [128]. The main advantage is the ability for targeted degradation of undruggable proteins in the CNS. PROTACs have higher specificity than other methods and can selectively degrade different isotypes of proteins expressed by the same gene. Furthermore, PROTACs bypass the potential toxic effects that can develop with pharmacological approaches. In fact, PROTACs can inactivate target-protein function without directly binding target proteins for long time periods. Moreover, PROTACs can be designed on the basis of catalytic reactions and consequently can be reused for many cycles until the target proteins in cells are eliminated. Furthermore, because PROTACs have sub-stoichiometric catalytic activity [129], administration of very low concentrations is sufficient to degrade a target protein. Therefore, developing active drugs by using PROTACs is highly feasible, and the inhibition of target protein does not require high concentrations of drug [130, 131]. Overall, PROTACs may be a highly effective method to target and destroy undruggable proteins involved in the pathophysiology of many CNS disorders including AD.

            6.2 Disadvantages

            Several limitations may prevent the development of PROTAC drugs for clinical applications in the future. Because PROTAC technology uses drugs for dual targets, the constructed compounds would have a high molecular weight for being easily synthesized [30, 131]. Therefore, they cannot be simply dissolved for oral absorption because of transmural issues, thus posing a major pharmacokinetic barrier. For example, a major issue is blood-brain-barrier permeability, a limiting factor in many pharmacological approaches. As described above, the efficacy study of the PROTAC C004019 (section 5.1.1) [53] suggests that PROTACs might also effectively penetrate the blood-brain barrier [30].

            Another possible limitation is localization of PROTACs to specific brain regions, as is desirable to combat neurodegenerative diseases such as AD. For successful use of PROTACs, the E3 ligase must be expressed in the target region. However, some E3 ligases (e.g., CRBN) [132] are differentially expressed across brain areas, thus potentially complicating disease treatment. For example, tau accumulation occurs progressively in the brain regions affected by AD, starting in the locus coeruleus and entorhinal cortex and ending in the primary visual cortex [133]. Therefore, depending on disease progression, PROTACs would need to precisely target tau in specific regions of the brain. Managing drugs for colocalization with and/or without expression of E3 ligase in the affected brain regions is challenging, and new technology is needed to solve this emerging concern [134]. Furthermore, many CNS disorders are associated with expansive decreases in proteasome catalytic activity [135]. Consequently, even if a PROTAC can ubiquitinate a POI, it still might not degrade the protein. Thus, decreased proteasome function remains a barrier to PROTAC-mediated degradation of target proteins divergently expressed in the brain for the treatment of AD.

            7. DISCUSSION

            PROTACs are a powerful and attractive strategy studied and developed in both academic and industrial settings. Recently, they have been widely investigated for the treatment of several diseases including cancer, neurodegeneration, immune disorders, cardiovascular dysfunction, fatty liver disease, and viral infections. Here, we discuss AD-specific PROTACs and several others that have been used for targeting aberrant proteins/signaling pathways that are dysregulated in the tumor microenvironment. However, because of their similar structures and mechanisms, we introduce these molecules as potential PROTACs for AD treatment. We reviewed two peptidic PROTACs developed for targeting tau in the treatment of AD [50, 51]. Although they degrade tau, the subunit protein of one of the major hallmarks of AD, their application has been limited, partly because of their intrinsic proneness to protease degradation and their poor membrane permeability in vivo. The stability of those peptides might be improved by substitution of unnatural amino acids, backbone modifications, and cyclization [136], and their cell-membrane permeability could be modified by increasing their lipophilicity and decreasing their hydrogen bonding [137]. Silva et al. have also established another type of PROTAC using a tau PET tracer as a warhead; however, application of these PROTACs has not been validated in vivo [52]). In fact, the construction of PROTACs such as warheads with high affinity toward target proteins might be not sufficient for the generation of active PROTACs [138]. Therefore, steric-structure induction by the binding of target protein to hijacked E3 ligase facilitates the transfer of ubiquitin from E2 to the target protein and potentiates PROTAC activity. This ternary complex enables PROTACs to degrade large molecules, such as protein aggregates, which normally cannot pass into the proteasome’s barrel-like structure for degradation [15]. Through this approach, Wang et al. have established the PROTAC C004019, which efficiently induces clearance of tau in the brain in hTau and 3×Tg-AD transgenic mice. Thus, C004019 may potentially pass through the proteasome’s barrel-like structure and cross the blood-brain barrier, unlike most large drugs. Although C004019 markedly improves synaptic and cognitive function in these mice, its selectivity for recognition of tau species (WT and phosphorylated tau) is poor, perhaps partly because of the structure of tau, which is a natively unfolded protein. Thus, new challenges exist to improve PROTAC capabilities.

            Although aging is a major cause of cancer and AD [139], some studies have revealed that AD pathogenesis protects against cancer, and vice versa, although the underlying mechanisms remain elusive [140, 141]. Notably, cancer and AD pathologically share common features. For example, a high level of cell-cycle re-entry, which is required for cancer pathogenesis, has also been observed in patients with AD [142, 143], but instead of cell division, the neuronal cell cycle is aborted, and cell death occurs [144, 145]. The activation of CDK2, CDK4, CDK5, and caspases is significantly elevated during the cell cycle, and results in APP phosphorylation, APP proteolysis, and Aβ production [146148]. The role of mTOR activation in the initiation of proliferation suggests its function in cell-cycle re-entry of neuronal cells and the pathogenesis of AD [149]. The activation of mTOR is also believed to drive neurodegeneration through tau activation [150], thereby leading to NFT accumulation. Moreover, inactivation of the mTOR pathway results in the activation of the activation of autophagy for clearance of Aβ from the cells [151]. In the brain tumor microenvironment, adenosine monophosphate protein kinase (AMPK) might be activated under energy stress and consequently result in the activation of FOXO3 [152] and the protection of neuronal cells. This energy stress is due to the high metabolomic rate of cancer cell proliferation and the hijacking of energy in the brain microenvironment. Meanwhile, mTOR signaling and consequent cell-cycle re-entry are inhibited by AMPK [153], and FOXO increases the expression of antioxidant enzymes, thereby decreasing cell damage [154, 155] and inhibiting neurodegeneration. Together, mTOR-mediated cell growth and proliferation not only drive cancer cell progression but also cause neuronal cell arrest. Therefore, targeting the PI3K/mTOR/AKT axis provides an excellent therapeutic option for the management of AD and tumor microenvironments ( Figure 7 ).

            Figure 7 |

            Therapeutic potential of the PI3K/AKT/mTOR axis for the management of AD and cancer.

            Over long-term physiological stimulation, such as aging followed by mitochondrial dysfunction, oxidative stress and metabolic stress might accumulate and trigger PI3K/AKT/mTOR signaling, thus resulting in strong activation of cell-cycle re-entry in neuronal cells. In contrast to cancer, in AD, the neuronal cell cycle is aborted, and cells proceed to death instead of division. Moreover, a significant elevation in CDK2, CDK4, and CDK5, and activation of caspases during cell-cycle re-entry leads to APP phosphorylation, APP proteolysis, and Aβ production. Furthermore, activation of the mTOR pathway inactivates autophagy, the process required for the clearance of Aβ in neuronal cells. After cancer cell proliferation in the brain, thus hijacking energy from neurons, this energy stress stimulates AMPK and activates FOXO3, which protects neuronal cells in the brain tumor microenvironment. FOXO increases the expression of antioxidant enzymes, which decrease the damage to neuronal cells. Dashed arrows require additional investigation of the molecular network in the indicated condition.

            In section 5.2, we briefly introduced several PROTACs established to target HIF1α, PI3K, AKT, and BET in the tumor microenvironment, with its aberrant signaling. Most of these PROTACs efficiently degrade their own target proteins, such as BET, with high sensitivity and selectivity. Therefore, the application of these PROTACs has great potential in targeting the AD microenvironment. Although cancer and AD pathologically share common features, their disease-causing mechanisms substantially differ. Given that most established PROTACs have been studied primarily in the cancer disease setting, their formulation and mechanisms of action should be carefully designed to combat AD. Currently, two PROTACs, ARV-110 and ARV-47, have been used in clinical trials for the treatment of prostate and breast cancer, respectively, by targeting of androgen receptor and estrogen receptor (from Arvinas). Both show acceptable safety, and ARV-471 has been found to be well tolerated at all tested dose levels without severe adverse effects. Interestingly, ARV-471 has a synergistic effect on tumor inhibition in combination treatment with kinase inhibitors such as CDK4/6 inhibitors. Therefore, the combination of PROTAC with chemotherapy, antibody therapy (in immunotherapy), and small-molecule inhibitors might provide an alternative approach for the treatment of diseases including cancer and AD.


            PROTAC technology enables the discovery of new therapeutic agents with the unique ability to degrade rather than inhibit “undruggable” proteins. They can be used to address several concerns associated with the use of traditional small molecules, which may have poor selectivity, and result in adverse effects and drug resistance. However, the toxicity of PROTACs may limit future drug development, partly because of the effects of off-target degradation. PROTACs completely degrade proteins via the UPS, whereas parental small molecules or compounds are required only to inhibit protein functions. Therefore, the combination of small molecules with a tissue-specific E3 ligase is highly advantageous for the selective degradation of target proteins. Moreover, the structure of PROTACs is generally complex, and their synthesis is complicated because of their high molecular weight (800–1000 kDa). These aspects should be recognized for further modification and screening to improve brain membrane permeability. Further optimization of the structure and synthesis of PROTACs is necessary to provide a stable platform for drug discovery. To this end, the application of crystallography may aid in understanding of the structural mechanisms of PROTACs. For example, structural analyses of the VHL and/or Cereblon E3 ligase proteins have demonstrated the shape and position of the Cullin-RING E3 ubiquitin ligase along with E2 and target proteins in detail, thus enabling ubiquitin transfer to be targeted [156].

            As described herein, confirming that all proteins of interest will be degraded by a PROTAC in the absence of ligands is impossible. Therefore, the selection of new ligands and validation of targets will be another focus in PROTAC development. More than 600 E3 ligases exist in the human genome, but only several have been used in PROTAC technology. Therefore, vast possibilities exist for expanding screening efforts to identify suitable E3 ligases. Furthermore, additional E3 ligases must be investigated to avoid off-target effects and rapid responses to brain diseases, particularly AD. Finally, recent advancements in CRISPR-dCas9 technology may be helpful to stimulate proteasome function in brain disorders with extensive decreases in proteasome catalytic activity [157]. Interestingly, IU1, a compound inhibiting ubiquitin-specific protease 14 (USP14), has been found to improve protein degradation in vitro [158] and in mouse brain tissue [159], although proteasome function is not broadly enhanced in the brain [160]. These findings suggest a viable avenue for careful design of combination therapies using PROTACs, monoclonal antibodies, RNA interferes, and/or small-molecule inhibitors to combat AD.

            9. DATA RETRIEVAL

            This review was accomplished through the use of electronic databases, such as PubMed, Scopus, and Web of Science, for finding articles associated with AD, aberrant signaling pathways, as well as the application of PROTACs. We used the keywords such as (“Alzheimer’s disease” OR “PROTAC” OR “ubiquitin proteasome system”, OR “therapeutic target”, OR “aberrant signaling”) (title/abstract/keywords). In general, the focus was on PROTACs affecting aberrant signaling pathways in AD. Data were gathered without date limitations until November 2021. The lists of references in the articles were also manually searched for aberrant signaling pathways recognized as crucial therapeutic targets in AD.


            Wenyi Wei is Co-Editor-in-Chief of Acta Materia Medica. He was not involved in the peer-review or handling of the manuscript. The other authors have no other competing interests to disclose.


            1. 2021 Alzheimer’s Disease Facts and Figures. Alzheimers Dementia. 2021. Vol. 17(3):327–406

            2. Alzheimer’s Association: 2009 Alzheimer’s Disease Facts and Figures. Alzheimers Dementia. 2009. Vol. 5(3):234–270

            3. Burns A, Iliffe S. Alzheimer’s Disease. Br Med J. 2009. Vol. 338:b158

            4. Zhu X, Lee HG, Perry G, Smith MA. Alzheimer Disease, the Two-hit Hypothesis: An Update. Biochimica et Biophysica Acta. 2007. Vol. 1772(4):494–502

            5. Murphy MP, LeVine H 3rd. Alzheimer’s Disease and the Amyloid-beta Peptide. Journal of Alzheimer’s Disease. 2010. Vol. 19(1):311–323

            6. Hartl FU. Protein Misfolding Diseases. Annual Review of Biochemistry. 2017. Vol. 86:21–26

            7. Hardy J, Selkoe DJ. The AMYLOID Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics. Science. 2002. Vol. 297(5580):353–356

            8. O’Brien RJ, Wong PC. Amyloid Precursor Protein Processing and Alzheimer’s Disease. Annual Review of Neuroscience. 2011. Vol. 34:185–204

            9. Alonso AC, Grundke-Iqbal I, Iqbal K. Alzheimer’s Disease Hyperphosphorylated Tau Sequesters Normal Tau into Tangles of Filaments and Disassembles Microtubules. Nature Medicine. 1996. Vol. 2(7):783–787

            10. Armstrong RA. The Molecular Biology of Senile Plaques and Neurofibrillary Tangles in Alzheimer’s Disease. Folia Neuropathol. 2009. Vol. 47(4):289–299

            11. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological Alterations in Alzheimer Disease. Cold Spring Harb Perspect Med. 2011. Vol. 1(1):a006189

            12. Pohl C, Dikic I. Cellular Quality Control by the Ubiquitin-proteasome System and Autophagy. Science. 2019. Vol. 366(6467):818–822

            13. Deol KK, Lorenz S, Strieter ER. Enzymatic Logic of Ubiquitin Chain Assembly. Frontiers in Physiology. 2019. Vol. 10:835

            14. Heride C, Urbe S, Clague MJ. Ubiquitin Code Assembly and Disassembly. Current Biology. 2014. Vol. 24(6):R215–R220

            15. Tai HC, Schuman EM. Ubiquitin, the Proteasome and Protein Degradation in Neuronal Function and Dysfunction. Nature Reviews Neuroscience. 2008. Vol. 9(11):826–838

            16. Ding Q, Cecarini V, Keller JN. Interplay Between Protein Synthesis and Degradation in the CNS: Physiological and Pathological Implications. Trends in Neurosciences. 2007. Vol. 30(1):31–36

            17. Kerr JS, Adriaanse BA, Greig NH, Mattson MP, Cader MZ, Bohr VA, et al.. Mitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms. Trends in Neurosciences. 2017. Vol. 40(3):151–166

            18. Feng Y, He D, Yao Z, Klionsky DJ. The Machinery of Macroautophagy. Cell Research. 2014. Vol. 24(1):24–41

            19. Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, et al.. Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. Neuron. 2017. Vol. 93(5):1015–1034

            20. Cheng J, Liao Y, Xiao L, Wu R, Zhao S, Chen H, et al.. Autophagy Regulates MAVS Signaling Activation in a Phosphorylation-dependent Manner in Microglia. Cell Death & Differentiation. 2017. Vol. 24(2):276–287

            21. Li Q, Liu Y, Sun M. Autophagy and Alzheimer’s Disease. Cellular and Molecular Neurobiology. 2017. Vol. 37(3):377–388

            22. Zare-Shahabadi A, Masliah E, Johnson GV, Rezaei N. Autophagy in Alzheimer’s disease. Reviews in the Neurosciences. 2015. Vol. 26(4):385–395

            23. Tian Y, Bustos V, Flajolet M, Greengard P. A Small-molecule Enhancer of Autophagy Decreases Levels of Abeta and APP-CTF via Atg5-dependent Autophagy Pathway. The FASEB Journal. 2011. Vol. 25(6):1934–1942

            24. Vingtdeux V, Chandakkar P, Zhao H, d’Abramo C, Davies P, Marambaud P. Novel Synthetic Small-molecule Activators of AMPK as Enhancers of Autophagy and Amyloid-Beta Peptide Degradation. The FASEB Jorunal. 2011. Vol. 25(1):219–231

            25. Boland B, Kumar A, Lee S, Platt FM, Wegiel J, Yu WH, et al.. Autophagy Induction and Autophagosome Clearance in Neurons: Relationship to Autophagic Pathology in Alzheimer’s Disease. The Journal of Neuroscience. 2008. Vol. 28(27):6926–6937

            26. Cromm PM, Crews CM. Targeted Protein Degradation: from Chemical Biology to Drug Discovery. Cell Chemical Biology. 2017. Vol. 24(9):1181–1190

            27. Schreiber SL. The Rise of Molecular Glues. Cell. 2021. Vol. 184(1):3–9

            28. Takahashi D, Moriyama J, Nakamura T, Miki E, Takahashi E, Sato A. AUTACs: Cargo-Specific Degraders Using Selective Autophagy. Molecular Cell. 2019. Vol. 76(5):797–810 e10

            29. Banik SM, Pedram K, Wisnovsky S, Ahn G, Riley NM, Bertozzi CR. Lysosome-targeting Chimaeras for Degradation of Extracellular Proteins. Nature. 2020. Vol. 584(7820):291–297

            30. Gu S, Cui D, Chen X, Xiong X, Zhao Y. PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery. Bioessays. 2018. Vol. 40(4):e1700247

            31. Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. Protacs: Chimeric Molecules that Target Proteins to the Skp1-Cullin-F Box Complex for Ubiquitination and Degradation. Proceedings of the National Academy of Sciences of the United States of America. 2001. Vol. 98(15):8554–8559

            32. Yang J, Li Y, Aguilar A, Liu Z, Yang CY, Wang S. Simple Structural Modifications Converting a Bona fide MDM2 PROTAC Degrader into a Molecular Glue Molecule: A Cautionary Tale in the Design of PROTAC Degraders. Journal of Medicinal Chemistry. 2019. Vol. 62(21):9471–9487

            33. An S, Fu L. Small-molecule PROTACs: An Emerging and Promising Approach for the Development of Targeted Therapy Drugs. EBioMedicine. 2018. Vol. 36:553–562

            34. Farnaby W, Koegl M, Roy MJ, Whitworth C, Diers E, Trainor N. BAF Complex Vulnerabilities in Cancer Demonstrated via Structure-based PROTAC Design. Nature Chemical Biology. 2019. Vol. 15(7):672–680

            35. Gadd MS, Testa A, Lucas X, Chan KH, Chen W, Lamont DJ, et al.. Structural Basis of PROTAC Cooperative Recognition for Selective Protein Degradation. Nature Chemical Biology. 2017. Vol. 13(5):514–521

            36. Nowak RP, DeAngelo SL, Buckley D, He Z, Donovan KA, An J, et al.. Plasticity in Binding Confers Selectivity in Ligand-induced Protein Degradation. Nature Chemical Biology. 2018. Vol. 14(7):706–714

            37. Riching KM, Mahan S, Corona CR, McDougall M, Vasta JD, Robers MB, et al.. Quantitative Live-Cell Kinetic Degradation and Mechanistic Profiling of PROTAC Mode of Action. ACS Chemical Biology. 2018. Vol. 13(9):2758–2770

            38. Smith BE, Wang SL, Jaime-Figueroa S, Harbin A, Wang J, Hamman BD, et al.. Differential PROTAC Substrate Specificity Dictated by Orientation of Recruited E3 Ligase. Nature Communications. 2019. Vol. 10(1):131

            39. Raina K, Lu J, Qian Y, Altieri M, Gordon D, Rossi AM, et al.. PROTAC-induced BET Protein Degradation as a Therapy for Castration-Resistant Prostate Cancer. Proceedings of the National Academy of Sciences of the United States of America. 2016. Vol. 113(26):7124–7129

            40. Salami J, Alabi S, Willard RR, Vitale NJ, Wang J, Dong H, et al.. Androgen Receptor Degradation by the Proteolysis-targeting Chimera ARCC-4 Outperforms Enzalutamide in Cellular Models of Prostate Cancer Drug Resistance. Communications Biology. 2018. Vol. 1:100

            41. Liu J, Ma J, Liu Y, Xia J, Li Y, Wang ZP, et al.. PROTACs: A Novel Strategy for Cancer Therapy. Seminars in Cancer Biology. 2020. Vol. 67(Pt 2):171–179

            42. Qi SM, Dong J, Xu ZY, Cheng XD, Zhang WD, Qin JJ. PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy. Frontiers in Pharmacology. 2021. Vol. 12:692574

            43. Kargbo RB. Treatment of Cancer and Alzheimer’s Disease by PROTAC Degradation of EGFR. ACS Medicinal Chemistry Letters. 2019. Vol. 10(8):1098–1099

            44. Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated Neurodegeneration in Alzheimer’s Disease and Related Disorders. Nature Reviews Neuroscience. 2007. Vol. 8(9):663–672

            45. Hof PR, Morrison JH. The Aging Brain: Morphomolecular Senescence of Cortical Circuits. Trends in Neurosciences. 2004. Vol. 27(10):607–613

            46. Jellinger KA. Neuropathological Aspects of Alzheimer Disease, Parkinson Disease and Frontotemporal Dementia. Neurodegenerative Diseases. 2008. Vol. 5(3-4):118–121

            47. Sergeant N, Bretteville A, Hamdane M, Caillet-Boudin ML, Grognet P, Bombois S, et al.. Biochemistry of Tau in Alzheimer’s Disease and Related Neurological Disorders. Expert Rev Proteomics. 2008. Vol. 5(2):207–224

            48. Tracy TE, Gan L. Tau-mediated Synaptic and Neuronal Dysfunction in Neurodegenerative Disease. Current Opinion in Neurobiology. 2018. Vol. 51:134–138

            49. Zhang , X , Gao F, Wang D, Li C, Fu Y, He W, et al.. Tau Pathology in Parkinson’s Disease. Frontiers in Neurology. 2018. Vol. 9:809

            50. Chu TT, Gao N, Li QQ, Chen PG, Yang XF, Chen YX, et al.. Specific Knockdown of Endogenous Tau Protein by Peptide-Directed Ubiquitin-Proteasome Degradation. Cell Chemical Biology. 2016. Vol. 23(4):453–461

            51. Lu M, Liu T, Jiao Q, Ji J, Tao M, Liu Y, et al.. Discovery of a Keap1-dependent Peptide PROTAC to Knockdown Tau by Ubiquitination-proteasome Degradation Pathway. European Journal of Medicinal Chemistry. 2018. Vol. 146:251–259

            52. Silva MC, Ferguson FM, Cai Q, Donovan KA, Nandi G, Patnaik D, et al.. Targeted Degradation of Aberrant tau in Frontotemporal Dementia Patient-derived Neuronal Cell Models. Elife. 2019. Vol. 8:e45457

            53. Wang W, Zhou Q, Jiang T, Li S, Ye J, Zheng J, et al.. A Novel Small-molecule PROTAC Selectively Promotes Tau Clearance to Improve Cognitive Functions in Alzheimer-like Models. Theranostics. 2021. Vol. 11(11):5279–5295

            54. Ueda K, Saitoh T, Mori H. Tissue-dependent alternative splicing of mRNA for NACP, the precursor of non-A beta component of Alzheimer’s disease amyloid. Biochemical and Biophysical Research Communications. 1994. Vol. 205(2):1366–1372

            55. Burre J, Sharma M, Sudhof TC. Cell Biology and Pathophysiology of Alpha-Synuclein. Cold Spring Harbor Perspectives in Medicine. 2018. Vol. 8(3):a024091

            56. Colosimo C, Morgante L, Antonini A, Barone P, Avarello TP, Bottacchi E, et al.. Non-motor Symptoms in Atypical and Secondary Parkinsonism: The PRIAMO Study. Journal of Neurology. 2010. Vol. 257(1):5–14

            57. Filippini A, Gennarelli M, Russo I. α-Synuclein and Glia in Parkinson’s Disease: A Beneficial or a Detrimental Duet for the Endo-Lysosomal System? Cellular and Molecular Neurobiology. 2019. Vol. 39(2):161–168

            58. Yokota O, Terada S, Ishizu H, Ujike H, Ishihara T, Nakashima H, et al.. NACP/alpha-synuclein, NAC, and beta-amyloid Pathology of Familial Alzheimer’s Disease with the E184D Presenilin-1 Mutation: a Clinicopathological Study of two Autopsy Cases. Acta Neuropathologica. 2002. Vol. 104(6):637–648

            59. Kargbo RB. PROTAC Compounds Targeting alpha-Synuclein Protein for Treating Neurogenerative Disorders: Alzheimer’s and Parkinson’s Diseases. ACS Medicinal Chemistry Letters. 2020. Vol. 11(6):1086–1087

            60. Harris AL. Hypoxia--a Key Regulatory Factor in Tumour Growth. Nature Reviews Cancer. 2002. Vol. 2(1):38–47

            61. Guo J, Chakraborty AA, Liu P, Gan W, Gan W, Inuzuka H, et al.. pVHL Suppresses Kinase Activity of Akt in a Proline-hydroxylation-dependent Manner. Science. 2016. Vol. 353(6302):929–932

            62. Safran M, Kaelin WG Jr. HIF Hydroxylation and the Mammalian Oxygen-sensing Pathway. The Journal of Clinical Investigation. 2003. Vol. 111(6):779–783

            63. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, et al.. C. Elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases that Regulate HIF by Prolyl Hydroxylation. Cell. 2001. Vol. 107(1):43–54

            64. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al.. HIFalpha Targeted for VHL-mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing. Science. 2001. Vol. 292(5516):464–468

            65. Rezaeian AH, Li CF, Wu CY, Zhang X, Delacerda J, You MJ, et al.. A Hypoxia-responsive TRAF6-ATM-H2AX Signalling Axis Promotes HIF1alpha Activation, Tumorigenesis and Metastasis. Nature Cell Biology. 2017. Vol. 19(1):38–51

            66. Rezaeian AH, Wang YH, Lin HK. DNA Damage Players are Linked to HIF-1alpha/hypoxia Signaling. Cell Cycle. 2017. Vol. 16(8):725–726

            67. Peers C, Dallas ML, Boycott HE, Scragg JL, Pearson HA, Boyle JP. Hypoxia and Neurodegeneration. Annals of the New Yourk Academy of Sciences. 2009. Vol. 1177:169–77

            68. Zhang CE, Yang X, Li L, Sui X, Tian Q, Wei W, et al.. Hypoxia-induced Tau Phosphorylation and Memory Deficit in Rats. Neurodegenerative Diseases. 2014. Vol. 14(3):107–116

            69. Guglielmotto M, Tamagno E, Danni O. Oxidative Stress and Hypoxia Contribute to Alzheimer’s Disease Pathogenesis: Two Sides of the Same Coin. TheScientificWorldJournal. 2009. Vol. 9:781–791

            70. Wouters BG, Koritzinsky M. Hypoxia Signalling Through mTOR and the Unfolded Protein Response in Cancer. Nature Reviews Cancer. 2008. Vol. 8(11):851–864

            71. Grammas P, Tripathy D, Sanchez A, Yin X, Luo J. Brain Microvasculature and Hypoxia-related Proteins in Alzheimer’s Disease. International Journal of Clinical and Experimental Pathology. 2011. Vol. 4(6):616–627

            72. Masson N, Ratcliffe PJ. Hypoxia Signaling Pathways in Cancer Metabolism: The Importance of Co-selecting Interconnected Physiological Pathways. Cancer & Metabolism. 2014. Vol. 2(1):3

            73. Bazan NG, Palacios-Pelaez R, Lukiw WJ. Hypoxia Signaling to Genes: Significance in Alzheimer’s Disease. Molecular Neurobiology. 2002. Vol. 26(2-3):283–298

            74. Green KN, Boyle JP, Peers C. Hypoxia Potentiates Exocytosis and Ca2+ Channels in PC12 Cells via Increased Amyloid beta Peptide Formation and Reactive Oxygen Species Generation. The Journal of Physiology. 2002. Vol. 541(Pt 3):1013–1023

            75. Pugh CW, Ratcliffe PJ. Regulation of Angiogenesis by Hypoxia: Role of the HIF System. Nature Medicine. 2003. Vol. 9(6):677–684

            76. Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, et al.. Hypoxia Facilitates Alzheimer’s Disease Pathogenesis by Up-regulating BACE1 Gene Expression. Proceedings of the National Academy of Sciences of the United States of America. 2006. Vol. 103(49):18727–1832

            77. Fang H, Zhang LF, Meng FT, Du X, Zhou JN. Acute Hypoxia Promote the Phosphorylation of Tau Via ERK Pathway. Neuroscience Letters. 2010. Vol. 474(3):173–177

            78. Liu Y, Liu F, Iqbal K, Grundke-Iqbal I, Gong CX. Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease. FEBS Letters. 2008. Vol. 582(2):359–364

            79. Mobasheri A, Richardson S, Mobasheri R, Shakibaei M, Hoyland JA. Hypoxia Inducible Factor-1 and Facilitative Glucose Transporters GLUT1 and GLUT3: Putative Molecular Components of the Oxygen and Glucose Sensing Apparatus in Articular Chondrocytes. Histology & Histopathology. 2005. Vol. 20(4):1327–1338

            80. Schneekloth JS Jr, Fonseca FN, Koldobskiy M, Mandal A, Deshaies R, Sakamoto K, et al.. Chemical Genetic Control of Protein Levels: Selective in vivo Targeted Degradation. Journal of the American Chemical Society. 2004. Vol. 126(12):3748–354

            81. Buckley DL, Gustafson JL, Van Molle I, Roth AG, Tae HS, Gareiss PC, et al.. Small-molecule Inhibitors of the Interaction Between the E3 Ligase VHL and HIF1alpha. Angewandte Chemie. 2012. Vol. 51(46):11463–11467

            82. Buckley DL, van Molle I, Gareiss PC, Tae HS, Michel J, Noblin DJ, et al.. Targeting the von Hippel-Lindau E3 Ubiquitin Ligase Using Small Molecules to Disrupt the VHL/HIF-1alpha Interaction. Journal of the American Chemical Society. 2012. Vol. 134(10):4465–4468

            83. Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017. Vol. 169(2):361–371

            84. Cornu M, Albert V, Hall MN. mTOR in Aging, Metabolism, and Cancer. Current Opinion in Genetics & Development. 2013. Vol. 23(1):53–62

            85. Chong ZZ, Maiese K. Mammalian Target of Rapamycin Signaling in Diabetic Cardiovascular Disease. Cardiovascular Diabetology. 2012. Vol. 11:45

            86. Sarkar S, Rubinsztein DC. Small Molecule Enhancers of Autophagy for Neurodegenerative Diseases. Molecular Omics. 2008. Vol. 4(9):895–901

            87. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Müller F. Genetics: Influence of TOR Kinase on Lifespan in C. Elegans. Nature. 2003. Vol. 426(6967):620

            88. Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, et al.. Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span. Science. 2009. Vol. 326(5949):140–144

            89. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, et al.. Rapamycin Increases Lifespan and Inhibits Spontaneous Tumorigenesis in Inbred Female Mice. Cell Cycle. 2011. Vol. 10(24):4230–4236

            90. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, et al.. Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila Melanogaster. Cell Metabolism. 2010. Vol. 11(1):35–46

            91. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al.. Rapamycin Fed Late in Life Extends Lifespan in Genetically Heterogeneous Mice. Nature. 2009. Vol. 460(7253):392–395

            92. Powers RW 3rd, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S. Extension of Chronological Life Span in yeast by Decreased TOR Pathway Signaling. Genes & Development. 2006. Vol. 20(2):174–184

            93. Robida-Stubbs S, Glover-Cutter K, Lamming DW, Mizunuma M, Narasimhan SD, Neumann-Haefelin E, et al.. TOR Signaling and Rapamycin Influence Longevity by Regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metabolism. 2012. Vol. 15(5):713–724

            94. Caccamo A, Magrì A, Medina DX, Wisely EV, López-Aranda MF, Silva AJ, et al.. mTOR Regulates Tau Phosphorylation and Degradation: Implications for Alzheimer’s Disease and Other Tauopathies. Aging Cell. 2013. Vol. 12(3):370–380

            95. Sontag JM, Sontag E. Protein Phosphatase 2A Dysfunction in Alzheimer’s Disease. Frontiers in Molecular Neuroscience. 2014. Vol. 7:16

            96. Kickstein E, Krauss S, Thornhill P, Rutschow D, Zeller R, Sharkey J, et al.. Biguanide Metformin Acts on Tau Phosphorylation Via mTOR/Protein Phosphatase 2A (PP2A) Signaling. Proceedings of the National Academy of Sciences of the United States of America. 2010. Vol. 107(50):21830–21835

            97. Pei JJ, An W-L, Zhou X-W, Nishimura T, Norberg J, Benedikz E, et al.. P70 S6 Kinase Mediates Tau Phosphorylation and Synthesis. FEBS Letters. 2006. Vol. 580(1):107–114

            98. Lafay-Chebassier C, Paccalin M, Page G, Barc-Pain S, Perault-Pochat MC, Gil R, et al.. mTOR/p70S6k Signalling Alteration by Abeta Exposure as Well as in APP-PS1 Transgenic Models and in Patients with Alzheimer’s Disease. Journal of Neurochemistry. 2005. Vol. 94(1):215–225

            99. Majumder S, Richardson A, Strong R, Oddo S. Inducing Autophagy by Rapamycin Before, But Not After, the Formation of Plaques and Tangles Ameliorates Cognitive Deficits. PLoS One. 2011. Vol. 6(9):e25416

            100. Burke JE, Williams RL. Synergy in Activating Class I PI3Ks. Trends in Biochemical Sciences. 2015. Vol. 40(2):88–100

            101. Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in Cancer: Divergent Roles of Isoforms, Modes of Activation and Therapeutic Targeting. Nature Reviews Cancer. 2015. Vol. 15(1):7–24

            102. Li W, Gao C, Zhao L, Yuan Z, Chen Y, Jiang Y. Phthalimide Conjugations for the Degradation of Oncogenic PI3K. European Journal of Medicinal Chemistry. 2018. Vol. 151:237–247

            103. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K Pathway in Human Disease. Cell. 2017. Vol. 170(4):605–635

            104. Sen T, Saha P, Jiang T, Sen N. Sulfhydration of AKT Triggers Tau-Phosphorylation by Activating Glycogen Synthase Kinase 3beta in Alzheimer’s Disease. Proccedings of the National Academy of Sciences of the United States of America. 2021. Vol. 118(42)

            105. You I, Erickson EC, Donovan KA, Eleuteri NA, Fischer ES, Gray NS, et al.. Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling. Cell Chemical Biology. 2020. Vol. 27(1):66–73 e7

            106. Embi N, Rylatt DB, Cohen P. Glycogen Synthase Kinase-3 from Rabbit Skeletal Muscle. Separation from Cyclic-AMP-Dependent Protein Kinase and Phosphorylase Kinase. European Journal of Biochemistry. 1980. Vol. 107(2):519–527

            107. L’Episcopo F, Drouin-Ouellet J, Tirolo C, Pulvirenti A, Giugno R, Testa N, et al.. GSK-3beta-Induced Tau Pathology Drives Hippocampal Neuronal Cell Death in Huntington’s Disease: Involvement of Astrocyte-Neuron Interactions. Cell Death & Disease. 2016. Vol. 7:e2206

            108. Phiel CJ, Wilson CA, Lee VM-Y, Klein PS. GSK-3alpha Regulates Production of Alzheimer’s Disease Amyloid-Beta Peptides. Nature. 2003. Vol. 423(6938):435–439

            109. Sirerol-Piquer M, Gomez-Ramos P, Hernández F, Perez M, Morán MA, Fuster-Matanzo A, et al.. GSK3beta Overexpression Induces Neuronal Death and a Depletion of the Neurogenic Niches in the Dentate Gyrus. Hippocampus. 2011. Vol. 21(8):910–922

            110. Maqbool M, Mobashir M, Hoda N. Pivotal Role of Glycogen Synthase Kinase-3: A Therapeutic Target for Alzheimer’s Disease. Eur J Med Chem. 2016. Vol. 107:63–81

            111. Beurel E, Grieco SF, Jope RS. Glycogen Synthase Kinase-3 (GSK3): Regulation, Actions, and Diseases. Pharmacology & Therapeutics. 2015. Vol. 148:114–131

            112. Eldar-Finkelman H. Glycogen Synthase Kinase 3: an Emerging Therapeutic Target. Trends in Molecular Medicine. 2002. Vol. 8(3):126–132

            113. Jope RS, Yuskaitis CJ, Beurel E. Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics. Neurochemical Research. 2007. Vol. 32(4-5):577–595

            114. Jiang X, Zhou J, Wang Y, Liu X, Xu K, Xu J, et al.. PROTACs Suppression of GSK-3beta, a Crucial Kinase in Neurodegenerative Diseases. European Journal of Medicinal Chemistry. 2021. Vol. 210:112949

            115. Cochran AG, Conery AR, Sims , 3rd RJ. Bromodomains: a New Target Class for Drug Development. Nature Reviews Drug Discovery. 2019. Vol. 18(8):609–628

            116. Hargreaves DC, Horng T, Medzhitov R. Control of Inducible Gene Expression by Signal-Dependent Transcriptional Elongation. Cell. 2009. Vol. 138(1):129–145

            117. Bao Y, Wu X, Chen J, Hu X, Zeng F, Cheng J, et al.. Brd4 Modulates the Innate Immune Response Through Mnk2-eIF4E Pathway-Dependent Translational Control of IkappaBalpha. Proceedings of the National Academy of Sciences of the United States of America. 2017. Vol. 114(20):E3993–E4001

            118. Belkina AC, Nikolajczyk BS, Denis GV. BET Protein Function is Required for Inflammation: Brd2 Genetic Disruption and BET Inhibitor JQ1 Impair Mouse Macrophage Inflammatory Responses. The Journal of Immunology. 2013. Vol. 190(7):3670–3678

            119. Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung C-W, et al.. Suppression of Inflammation by a Synthetic Histone Mimic. Nature. 2010. Vol. 468(7327):1119–1123

            120. Xu Y, Vakoc CR. Brd4 is on the Move During Inflammation. Trends in Cell Biology. 2014. Vol. 24(11):615–616

            121. Magistri M, Velmeshev D, Makhmutova M, Patel P, Sartor GC, Volmar C-H, et al.. The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer’s Disease. Current Alzheimer Research. 2016. Vol. 13(9):985–995

            122. Benito E, Ramachandran B, Schroeder H, Schmidt G, Urbanke H, Burkhardt S, et al.. The BET/BRD Inhibitor JQ1 Improves Brain Plasticity in WT and APP Mice. Translational Psychiatry. 2017. Vol. 7(9):e1239

            123. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, et al.. DRUG DEVELOPMENT. Phthalimide Conjugation as a Strategy for In vivo Target Protein Degradation. Science. 2015. Vol. 348(6241):1376–1381

            124. DeMars KM, Yang C, Candelario-Jalil E. Neuroprotective Effects of Targeting BET Proteins for Degradation with dBET1 in Aged Mice Subjected to Ischemic Stroke. Neurochemistry International. 2019. Vol. 127:94–102

            125. DeMars KM, Yang C, Castro-Rivera CI, Candelario-Jalil E. Selective Degradation of BET Proteins with dBET1, a Proteolysis-Targeting Chimera, Potently Reduces Pro-Inflammatory Responses in Lipopolysaccharide-Activated Microglia. Biochemical and Biophysical Research Communications. 2018. Vol. 497(1):410–415

            126. Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, et al.. Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chemistry & Biology. 2015. Vol. 22(6):755–763

            127. Zengerle M, Chan KH, Ciulli A. Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4. ACS Chemical Biology. 2015. Vol. 10(8):1770–1777

            128. Wang Y, Jiang X, Feng F, Liu W, Sun H. Degradation of Proteins by PROTACs and Other Strategies. Acta Pharmaceutica Sinica B. 2020. Vol. 10(2):207–238

            129. Bondeson DP, Mares A, Smith IED, Ko E, Campos S, Miah AH, et al.. Catalytic In vivo Protein Knockdown by Small-Molecule PROTACs. Nature Chemical Biology. 2015. Vol. 11(8):611–617

            130. Churcher I. Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones? Journal of Medicinal Chemistry. 2018. Vol. 61(2):444–452

            131. Crews CM. Inducing Protein Degradation as a Therapeutic Strategy. Journal of Medicinal Chemistry. 2018. Vol. 61(2):403–404

            132. Higgins JJ, Tal AL, Sun X, Hauck SCR, Hao J, Kosofosky BE, et al.. Temporal and Spatial Mouse Brain Expression of Cereblon, an Ionic Channel Regulator Involved in Human Intelligence. Journal of Neurogenetics. 2010. Vol. 24(1):18–26

            133. Franzmeier N, Neitzel J, Rubinski A, Smith R, Strandberg O, Ossenkoppele R, et al.. Functional Brain Architecture is Associated with the Rate of Tau Accumulation in Alzheimer’s Disease. Nature Communications. 2020. Vol. 11(1):347

            134. Rich MC, Sherwood J, Bartley AF, Whitsitt QA, Lee M, Willoughby WR, et al.. Focused Ultrasound Blood Brain Barrier Opening Mediated Delivery of MRI-Visible Albumin Nanoclusters to the Rat Brain for Localized Drug Delivery with Temporal Control. Journal of Controlled Release. 2020. Vol. 324:172–180

            135. Thibaudeau TA, Anderson RT, Smith DM. A Common Mechanism of Proteasome Impairment by Neurodegenerative Disease-Associated Oligomers. Nature Communications. 2018. Vol. 9(1):1097

            136. Yao JF, Yang H, Zhao Y-Z, Xue M. Metabolism of Peptide Drugs and Strategies to Improve their Metabolic Stability. Current Drug Metabolism. 2018. Vol. 19(11):892–901

            137. Di L. Strategic Approaches to Optimizing Peptide ADME Properties. The AAPS Journal. 2015. Vol. 17(1):134–143

            138. Konstantinidou M, Li J, Zhang B, Wang Z, Shaabani S, Brake FT, et al.. PROTACs- a Game-Changing Technology. Expert Opinion on Drug Discovery. 2019. Vol. 14(12):1255–1268

            139. Guerreiro R, Bras J. The Age Factor in Alzheimer’s Disease. Genome Medicine. 2015. Vol. 7:106

            140. Musicco M, Adorni F, Di Santo S, Prinelli F, Pettenati C, Caltagirone C, et al.. Inverse Occurrence of Cancer and Alzheimer Disease: A Population-Based Incidence Study. Neurology. 2013. Vol. 81(4):322–328

            141. Romero JP, Benito-León J, Louis ED, Bermejo-Pareja F. Alzheimer’s Disease is Associated with Decreased Risk of Cancer-Specific Mortality: A Prospective Study (NEDICES). Journal of Alzheimers Disease. 2014. Vol. 40(2):465–473

            142. Klein JA, Ackerman SL. Oxidative Stress, Cell Cycle, and Neurodegeneration. The Journal of Clinical Investigation. 2003. Vol. 111(6):785–793

            143. Kruman II. Why do Neurons Enter the Cell Cycle? Cell Cycle. 2004. Vol. 3(6):769–773

            144. McShea A, Lee H-G, Petersen RB, Casadesus G, Vincent I, Linford NJ, et al.. Neuronal Cell Cycle Re-Entry Mediates Alzheimer Disease-Type Changes. Biochimica et Biophysica Acta. 2007. Vol. 1772(4):467–472

            145. Yang Y, Mufson EJ, Herrup K. Neuronal Cell Death is Preceded by Cell Cycle Events at All Stages of Alzheimer’s Disease. The Journal of Neuroscience. 2003. Vol. 23(7):2557–2563

            146. Judge M, Hornbeck L, Potter H, Padmanabhan J. Mitosis-Specific Phosphorylation of Amyloid Precursor Protein at Threonine 668 Leads to its Altered Processing and Association with Centrosomes. Molecular Neurodegeneration. 2011. Vol. 6:80

            147. Liu F, Su Y, Li B, Zhou Y, Ryder J, Gonzalez-DeWhitt P, et al.. Regulation of Amyloid Precursor Protein (APP) Phosphorylation and Processing by p35/Cdk5 and p25/Cdk5. FEBS Letters. 2003. Vol. 547(1-3):193–196

            148. Folch J, Junyent F, Verdaguer E, Auladell C, Pizarro JG, Beas-Zarate C, et al.. Role of Cell Cycle Re-Entry in Neurons: A Common Apoptotic Mechanism of Neuronal Cell Death. Neurotoxicity Research. 2012. Vol. 22(3):195–207

            149. Norambuena A, Wallrabe H, McMahon L, Silva A, Swanson E, KhanSS , et al.. mTOR and Neuronal Cell Cycle Reentry: How Impaired Brain Insulin Signaling Promotes Alzheimer’s Disease. Alzheimer’s & Dementia. 2017. Vol. 13(2):152–167

            150. Rogaeva E, Kawarai T, George-Hyslop PS. Genetic Complexity of Alzheimer’s Disease: Successes and Challenges. Journal of Alzheimer’s Disease. 2006. Vol. 9 3 Suppl:381–387

            151. Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, et al.. Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-Beta Levels in a Mouse Model of Alzheimer’s Disease. PLoS One. 2010. Vol. 5(4):e9979

            152. Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP, et al.. The Energy Sensor AMP-Activated Protein Kinase Directly Regulates the Mammalian FOXO3 Transcription Factor. The Journal of Biological Chemistry. 2007. Vol. 282(41):30107–30119

            153. Xu J, Ji J, Yan XH. Cross-Talk between AMPK and mTOR in Regulating Energy Balance. Critical Reviews in Food Science and Nutrition. 2012. Vol. 52(5):373–381

            154. Gomez-Crisostomo NP, Rodriguez Martinez E, Rivas-Arancibia S. Oxidative Stress Activates the Transcription Factors FoxO 1a and FoxO 3a in the Hippocampus of Rats Exposed to Low Doses of Ozone. Oxidative Medicine and Cellular Longevity. 2014. Vol. 2014:805764

            155. Hay N. Interplay between FOXO, TOR, and Akt. Biochimca et Biophysica Acta. 2011. Vol. 1813(11):1965–1970

            156. Schapira M, Calabrese MF, Bullock AN, Crews CM. Targeted Protein Degradation: Expanding the Toolbox. Nature Reviews. Drug Discovery. 2019. Vol. 18(12):949–963

            157. Devulapalli R, Jones N, Farrell K, Musaus M, Kugler H, McFadden T, et al.. Males and Females Differ in the Regulation and Engagement of, but not Requirement for, Protein Degradation in the Amygdala During Fear Memory Formation. Neurobiology of Learning and Memory. 2021. Vol. 180:107404

            158. Lee BH, Lee MJ, Park S, Oh D-C, Elsasser S, Chen P-C, et al.. Enhancement of Proteasome Activity by a Small-Molecule Inhibitor of USP14. Nature. 2010. Vol. 467(7312):179–184

            159. Min JW, Lü L, Freeling JL, Martin DS, Wang H. USP14 Inhibitor Attenuates Cerebral Ischemia/Reperfusion-Induced Neuronal Injury in Mice. Journal of Neurochemistry. 2017. Vol. 140(5):826–833

            160. Jarome TJ, Kwapis JL, Hallengren JJ, Wilson SM, Helmstetter FJ. The Ubiquitin-Specific Protease 14 (USP14) is a Critical Regulator of Long-Term Memory Formation. Learning and Memory. 2013. Vol. 21(1):9–13

            161. Zerbinatti CV, Bu G. LRP and Alzheimer’s Disease. Reviews in the Neurosciences. 2005. Vol. 16(2):123–135

            162. Wang JZ, Wu Q, Smith A, Grundke-Iqbal I, Iqbal K. Tau is Phosphorylated by GSK-3 at Several Sites Found in Alzheimer Disease and its Biological Activity Markedly Inhibited only after it is Prephosphorylated by A-Kinase. FEBS Letters. 1998. Vol. 436(1):28–34

            163. Mahaman YAR, Huang F, Afewerky HK, Salissou Maibouge TM, Ghose B, Wang X. Involvement of Calpain in the Neuropathogenesis of Alzheimer’s Disease. Medicinal Research Reviews. 2019. Vol. 39(2):608–630

            164. Zundorf G, Reiser G. Calcium Dysregulation and Homeostasis of Neural Calcium in the Molecular Mechanisms of Neurodegenerative Diseases Provide Multiple Targets for Neuroprotection. Antioxid Redox Signal. 2011. Vol. 14(7):1275–1288

            Author and article information

            Acta Materia Medica
            Compuscript (Ireland )
            21 January 2022
            : 1
            : 1
            : 24-41
            [a ]Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
            Author notes
            *Correspondence: wwei2@ 123456bidmc.harvard.edu (W. Wei); arezaeia@ 123456bidmc.harvard.edu (A.-H. Rezaeian)
            Copyright © 2022 The Authors.

            Creative Commons Attribution 4.0 International License

            : 22 November 2021
            : 20 December 2021
            : 22 December 2021
            Page count
            Figures: 7, Tables: 1, References: 164, Pages: 18
            Funded by: US National Institutes of Health (NIH)
            Award ID: R35CA253027
            We sincerely thank our colleagues for critical reading of the manuscript. We apologize for not including all studies associated with AD and PROTACs in this review, because of space limitations. This study was partially supported by US National Institutes of Health (NIH) grants to W.W. (R35CA253027).

            Toxicology,Pathology,Biochemistry,Clinical chemistry,Pharmaceutical chemistry,Pharmacology & Pharmaceutical medicine
            alzheimer’s disease,protein degradation,PROTAC,autophagy,ubiquitin-proteasome system


            Comment on this article