GAPDH: β-Amyloid Mediated Iron Accumulation in Alzheimer’s Disease: A New Paradigm for Oxidative Stress Induction in Neurodegenerative Disorders

Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized clinically by dementia, loss of memory, and cognitive dysfunction. Although a number of molecular, biochemical, and cellular defects have been identified, the exact molecular mechanism(s) which underlie this disease are unknown. Of particular interest may be aberrant protein–protein interactions, especially with the amyloid protein which may lead not only to plaque development but also to alterations in cell function due to protein depletion. In that regard, recent evidence suggests a specific interaction of the β-amyloid precursor protein (β-APP) and the β-amyloid protein (β-AP) with glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The latter was thought to be a classical glycolytic protein of seemingly little interest. However, recent studies suggest that it is a multifunctional protein with diverse activities independent of its role in energy production. Further, it exhibits a diverse subcellular localization in the nucleus, membrane, and cytosol which may be not only directly related to its functional diversity but also may represent an intracellular equilibrium in the regulation of GAPDH expression. Accordingly, we shall consider the hypothesis that the formation of β-APP or β-AP–GAPDH protein–protein complexes alters both GAPDH function and its subcellular distribution. In particular, as recent studies indicate a fundamental role for membrane GAPDH in cellular iron uptake, transport, and metabolism, the formation of either β-APP–GAPDH or β-AP–GAPDH complexes may facilitate iron accumulation (a known characteristic of Alzheimer’s disease), thereby increasing oxidative stress as a consequence of an intracellular Fenton reaction. This pleiotropic effect of GAPDH binding could serve as a unifying hypothesis providing an initiating event in AD.