47
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      TNF-α-dependent neuronal necroptosis regulated in Alzheimer's disease by coordination of RIPK1-p62 complex with autophagic UVRAG

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background: Neuronal death is a major hallmark of Alzheimer's disease (AD). Necroptosis, as a programmed necrotic process, is activated in AD. However, what signals and factors initiate necroptosis in AD is largely unknown.

          Methods: We examined the expression levels of critical molecules in necroptotic signaling pathway by immunohistochemistry (IHC) staining and immunoblotting using brain tissues from AD patients and AD mouse models of APP/PS1 and 5×FAD. We performed brain stereotaxic injection with recombinant TNF-α, anti-TNFR1 neutralizing antibody or AAV-mediated gene expression and knockdown in APP/PS1 mice. For in vitro studies, we used TNF-α combined with zVAD-fmk and Smac mimetic to establish neuronal necroptosis models and utilized pharmacological or molecular biological approaches to study the signaling pathways.

          Results: We find that activated neuronal necroptosis is dependent on upstream TNF-α/TNFR1 signaling in both neuronal cell cultures and AD mouse models. Upon TNF-α stimulation, accumulated p62 recruits RIPK1 and induces its self-oligomerization, and activates downstream RIPK1/RIPK3/MLKL cascade, leading to neuronal necroptosis. Ectopic accumulation of p62 is caused by impaired autophagy flux, which is mediated by UVRAG downregulation during the TNF-α-promoted necroptosis. Notably, UVRAG overexpression inhibits neuronal necroptosis in cell and mouse models of AD.

          Conclusions: We identify a finely controlled regulation of neuronal necroptosis in AD by coordinated TNF-α signaling, RIPK1/3 activity and autophagy machinery. Strategies that could fine-tune necroptosis and autophagy may bring in promising therapeutics for AD.

          Related collections

          Most cited references64

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

          The amyloid hypothesis of Alzheimer's disease at 25 years

          Abstract Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.
            Bookmark
            • Record: found
            • Abstract: not found
            • Article: not found

            Mechanism and medical implications of mammalian autophagy

              Bookmark
              • Record: found
              • Abstract: not found
              • Article: not found

              Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).

                Bookmark

                Author and article information

                Journal
                Theranostics
                Theranostics
                thno
                Theranostics
                Ivyspring International Publisher (Sydney )
                1838-7640
                2021
                13 September 2021
                : 11
                : 19
                : 9452-9469
                Affiliations
                [1 ]Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
                [2 ]Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, 510632, China.
                [3 ]Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway.
                [4 ]The Norwegian Centre on Healthy Ageing (NO-Age), Oslo, Norway.
                [5 ]Department of Biochemistry, Chungnam National University, Daehak-ro 99, Yuseong-gu, Daejeon.
                [6 ]Laboratory for Neuroscience in Health and Disease, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China.
                [7 ]Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, 210009, China.
                [8 ]Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
                Author notes
                ✉ Corresponding author: J. S. (E-mail: simajian@ 123456cpu.edu.cn ).

                #These authors contributed equally to this work.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                thnov11p9452
                10.7150/thno.62376
                8490500
                34646380
                12194d92-5480-4bdb-9d22-e1ae2306955c
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 6 May 2021
                : 5 September 2021
                Categories
                Research Paper

                Molecular medicine
                alzheimer's disease,neuronal necroptosis,tnf-α/tnfr1 signaling,ripk1/ripk3/mlkl cascade,autophagic flux,p62,uvrag

                Comments

                Comment on this article