Association and heterogeneity at the GAPDH locus in Alzheimer's disease

Abstract

Glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH) and its paralogues were implicated in late-onset Alzheimer's disease (LOAD), although the strength and direction of association have not been consistent. We genotyped three previously reported SNPs (rs3741916-GAPDH 5'UTR, rs2029721-pGAPD and rs4806173-GAPDHS) in three case-control series (2112 cases and 3808 controls). Rs3741916 showed the strongest LOAD association (p=0.003). The minor allele of rs3741916 showed a protective effect in our combined series (OR=0.87, 95% confidence interval (CI)=0.79-0.96). This is consistent with results from the two published follow-up studies and in © 2010 Elsevier Inc. All rights reserved. # To whom correspondence should be address: taner.nilufer@mayo.edu or younkin.steven@mayo.edu, ). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Figure A and Supplemental Data Information: Supplementary Text, Search Terms

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

“…To date, several lines of evidence point to an association between GAPDH and AD (18,20,33,34). In post-mortem brain samples from AD patients, GAPDH has been found in senile plaques, and disulfide-bonded GAPDH aggregates have been found in the detergent-insoluble fraction (17,18).…”

Oxidation of an Exposed Methionine Instigates the Aggregation of Glyceraldehyde-3-phosphate Dehydrogenase

“…For instance, insoluble aggregates of GAPDH have been observed in the affected tissues of patients with Alzheimer disease (13) and alcoholic liver cirrhosis (12). Interestingly, GAPDH is also a susceptibility locus for late onset Alzheimer disease (21). Furthermore, robust aggregation of GAPDH has been detected in rodent models of motor neuron disease (17) and methamphetamine abuse (11).…”

Structural Characterization of Heparin-induced Glyceraldehyde-3-phosphate Dehydrogenase Protofibrils Preventing α-Synuclein Oligomeric Species Toxicity

“…However, recent data suggest that GADPH also possesses highly diverse nonglycolitic functions in the intra-or extracellular space (15) and has also been related to neurodegenerative diseases (16 -22). Moreover, genomic analysis suggests that GAPDH has a protective effect on late-onset Alzheimer disease (23). On the other hand, GAGs are present in most, if not all, types of amyloids inside and outside of the cells (24,25).…”