Extracellular gapdh promotes alzheimer disease progression by enhancing amyloid-β aggregation and cytotoxicity

Vladimir F. Lazarev, Magda Tsolaki, Elena R. Mikhaylova, Konstantin A. Benken, Maxim A. Shevtsov, Alina D. Nikotina, Mirna Lechpammer, Vladimir A. Mitkevich, Alexander A. Makarov, Alexey A. Moskalev, Sergey A. Kozin, Boris A. Margulis, Irina V. Guzhova, Evgeny Nudler

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Neuronal cell death at late stages of Alzheimer's disease (AD) causes the release of cytosolic proteins. One of the most abundant such proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), forms stable aggregates with extracellular amyloid-β (Aβ). We detect 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 cells, neural 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 from animals with enhanced GAPDH expression demonstrates 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. These findings argue that extracellular GAPDH compromises Aβ clearance and accelerates neurodegeneration, and, thus, is a promising pharmacological target for AD.

Original languageEnglish (US)
Pages (from-to)1223-1237
Number of pages15
JournalAging and Disease
Volume12
Issue number5
DOIs
StatePublished - Aug 1 2021
Externally publishedYes

Keywords

  • Alzheimer's disease (AD)
  • Amyloid-β (Aβ)
  • Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Geriatrics and Gerontology
  • Clinical Neurology
  • Cell Biology

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