Extracellular GAPDH Promotes Alzheimer Disease Progression by Enhancing Amyloid-β Aggregation and Cytotoxicity

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-beta (A beta). 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 A beta that is mediated by transglutaminase (tTG). The Q15A substitution weakens the interaction between A beta and GAPDH and reduces A beta-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 A beta-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 A beta aggregates and reversed memory deficit in AD transgenic mice. These findings argue that extracellular GAPDH compromises A. clearance and accelerates neurodegeneration, and, thus, is a promising pharmacological target for AD.

Automated summary

The study revealed that the interaction between glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and amyloid-beta (A beta) contributes to neurodegeneration in Alzheimer's disease (AD) patients. By investigating the relationship between A beta and GAPDH, potential therapeutic targets were identified through reversing the pathogenic abnormalities associated with AD.