Glyceraldehyde-3-phosphate Dehydrogenase Aggregates Accelerate Amyloid-? Amyloidogenesis in Alzheimer Disease.

ABSTRACT: Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by loss of neurons and formation of pathological extracellular deposits induced by amyloid-? peptide (A?). Numerous studies have established A? amyloidogenesis as a hallmark of AD pathogenesis, particularly with respect to mitochondrial dysfunction. We have previously shown that glycolytic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) forms amyloid-like aggregates upon exposure to oxidative stress and that these aggregates contribute to neuronal cell death. Here, we report that GAPDH aggregates accelerate A? amyloidogenesis and subsequent neuronal cell death both in vitro and in vivo. Co-incubation of A?40 with small amounts of GAPDH aggregates significantly enhanced A?40 amyloidogenesis, as assessed by in vitro thioflavin-T assays. Similarly, structural analyses using Congo red staining, circular dichroism, and atomic force microscopy revealed that GAPDH aggregates induced A?40 amyloidogenesis. In PC12 cells, GAPDH aggregates augmented A?40-induced cell death, concomitant with disruption of mitochondrial membrane potential. Furthermore, mice injected intracerebroventricularly with A?40 co-incubated with GAPDH aggregates exhibited A?40-induced pyramidal cell death and gliosis in the hippocampal CA3 region. These observations were accompanied by nuclear translocation of apoptosis-inducing factor and cytosolic release of cytochrome c from mitochondria. Finally, in the 3×Tg-AD mouse model of AD, GAPDH/A? co-aggregation and mitochondrial dysfunction were consistently detected in an age-dependent manner, and A? aggregate formation was attenuated by GAPDH siRNA treatment. Thus, this study suggests that GAPDH aggregates accelerate A? amyloidogenesis, subsequently leading to mitochondrial dysfunction and neuronal cell death in the pathogenesis of AD.

SUBMITTER: Itakura M 

PROVIDER: S-EPMC4646260 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature