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- W4243921197 abstract "Abstract Background Neuronal cell death during Alzheimer disease (AD) causes the release of cytosolic proteins, particularly glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which forms highly cytotoxic detergent-insoluble complexes with amyloid-β (Aβ) and promotes neurodegeneration. Methods We detected and quantified the complex formation between Aβ and GAPDH released from brain tissue of patients with AD using ultrafiltration, and fluorescence resonance energy transfer (FRET). To explore the biochemical and structural features of Aβ-GAPDH complexes we employed novel immunoenzyme assays and atomic force microscopy. Lentiviral infection in situ was used to elevate GAPDH in brain tissue of rat and mouse models of AD. The Morris maize water test, MRI, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and lactate dehydrogenase (LDH)-activity assays were used to characterize the effects of Aβ-GAPDH complexes in animal and cellular models of AD. Results Here we report that GAPDH forms stable aggregates with extracellular Aβ. We detected these aggregates in cerebrospinal fluid (CSF) from AD patients at levels directly proportional to the progressive stages of AD. We found that GAPDH forms a covalent bond with Q15 of Aβ that is mediated by transglutaminase (tTG). The Q15A substitution weakens the interaction between Aβ and GAPDH and reduces Aβ-GAPDH cytotoxicity. Lentivirus-driven GAPDH overexpression in two AD animal models increased the level of apoptosis of hippocampal neurons, neuronal degeneration, and cognitive dysfunction. In contrast, in vivo knockdown of GAPDH reversed these pathogenic abnormalities suggesting a pivotal role of GAPDH in Aβ-stimulated neurodegeneration. CSF obtained from animals with enhanced GAPDH expression demonstrated increased cytotoxicity in vitro . Furthermore, RX-624, a specific GAPDH small molecular ligand reduced accumulation of Aβ aggregates and reversed memory deficit in AD transgenic mice. Conclusions Extracellular GAPDH compromises Aβ clearance and accelerates neurodegeneration, thus representing a promising pharmacological target for AD." @default.
- W4243921197 created "2022-05-12" @default.
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- W4243921197 date "2020-08-18" @default.
- W4243921197 modified "2023-09-27" @default.
- W4243921197 title "Extracellular GAPDH promotes Alzheimer disease progression by enhancing amyloid-β aggregation and cytotoxicity" @default.
- W4243921197 doi "https://doi.org/10.21203/rs.3.rs-53359/v1" @default.
- W4243921197 hasPublicationYear "2020" @default.
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