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      Improved Brain Insulin/IGF Signaling and Reduced Neuroinflammation with T3D-959 in an Experimental Model of Sporadic Alzheimer’s Disease

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          Abstract

          Alzheimer's disease (AD) is associated with progressive impairments in brain insulin, insulin-like growth factor (IGF), and insulin receptor substrate (IRS) signaling through Akt pathways that regulate neuronal growth, survival, metabolism, and plasticity. The intracerebral streptozotocin (i.c. STZ) model replicates the full range of abnormalities in sporadic AD. T3D-959, an orally active PPAR-delta/gamma agonist remediates neurocognitive deficits and AD neuropathology in the i.c. STZ model.

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          Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimer's Disease

          Suzanne M de la Monte (2012)
          Alzheimer's disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades.
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            Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer's disease.

            Marisa De Feo, Ming Tong, Jack R. Wands … (2006)
            Alzheimer's disease (AD) is associated with major impairments in insulin and insulin-like growth factor (IGF) gene expression and signaling in the brain. These abnormalities increase with severity of dementia, and are associated with deficiencies in energy metabolism and acetylcholine homeostasis. The co-existence of brain insulin/IGF deficiency and resistance suggests that AD may represent a brain-specific form of diabetes, i.e. Type 3 diabetes. This hypothesis is supported by the findings in an experimental animal model in which intracerebral (ic) Streptozotocin (STZ) was used to deplete brain and not pancreatic insulin. The ic-STZ treatment produced brain-specific insulin depletion and insulin resistance are associated with progressive neurodegeneration that shares many features in common with AD. We now demonstrate that early treatment with peroxisome-proliferator activated receptor agonists can effectively prevent ic-STZ-induced neurodegeneration and its associated deficits in learning and memory. These effects were mediated by increased binding to insulin receptors, reduced levels of oxidative stress and tau phosphorylation, and increased choline acetyltransferase expression in the brain, suggesting that insulin sensitizer agents may have therapeutic efficacy in early AD.
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              The ubiquitin-proteasome system in Alzheimer's disease

              Salvatore Oddo (2008)
              Abstract Accumulation of proteins is a recurring event in many neurodegenerative diseases, including Alzheimer's disease (AD).Evidence has suggested that protein accumulation may result from a dysfunction in the ubiquitin proteasome system (UPS). Indeed, there is clear genetic and biochemical evidence of an involvement of the ubiquitin proteasome system in AD. This review summarizes the data supporting an involvement of the UPS in the pathogenesis of AD, focusing on the data showing the relationship between Aβ and tau, the two hallmark lesions of AD, and the UPS.
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                Author and article information

                Journal
                Title: Journal of Alzheimer's Disease
                Abbreviated Title: JAD
                Publisher: IOS Press
                ISSN (Print): 13872877
                ISSN (Electronic): 18758908
                Publication date Created: November 19 2016
                Publication date (Print): November 19 2016
                Volume: 55
                Issue: 2
                Pages: 849-864
                Affiliations
                [1 ]Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
                [2 ]Division of Gastroenterology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
                [3 ]Division of Neuropathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
                [4 ]Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
                [5 ]Department of Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
                [6 ]Quinnipiac University, Biomedical Sciences Department in Hamden, CT, USA
                [7 ]T3D Therapeutics, Inc., Research Triangle Park, NC, USA
                Article
                DOI: 10.3233/JAD-160656
                PMC ID: 5575806
                PubMed ID: 27802237
                SO-VID: 6c98f932-49b4-4b9e-afb9-3d0208d91f50
                Copyright © © 2016
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