Abstract
The regulation of glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) has been implicated both in age‐related neurodegenerative disease and in apoptosis. Previous in vitro studies suggest an interaction between GAPDH and the β‐amyloid precursor protein (β‐APP), a protein directly involved in Alzheimer's disease (AD). New studies indicate that GAPDH is a multidimensional protein with diverse membrane, cytoplasmic, and nuclear functions; each is distinct from its role in glycolysis. The nuclear functions of GAPDH include a role in apoptosis that requires its translocation to the nucleus. Accordingly, β‐APP–GAPDH interactions, altering GAPDH structure in vivo, may affect energy generation, inducing hypometabolism, a characteristic AD phenotype. Because GAPDH is a multifunctional protein, pleiotropic effects may also occur in a variety of fundamental cellular pathways in AD cells. This may include unique GAPDH–RNA interactions. We report here the identification of a high‐molecular‐weight (HMW) GAPDH species present exclusively in the postnuclear fraction of AD cells. The latter is characterized by reduced GAPDH activity. The HMW GAPDH species was not detected in postnuclear age‐matched control (AMC) fractions nor in AD whole‐cell preparations. Each is characterized by normal GAPDH activity. By definition, the preparation of whole‐cell extracts entails the destruction of subcellular structure. The latter findings indicate that the dissociation of the GAPDH protein from the HMW species restores its enzymatic activity. Thus, these results reveal a new, unique intracellular phenotype in AD cells. The functional consequences of subcellular alteration in GAPDH structure in AD cells are considered. © 2002 Wiley‐Liss, Inc.