Rat Brain Glyceraldehyde‐3‐Phosphate Dehydrogenase Interacts with the Recombinant Cytoplasmic Domain of Alzheimer's β‐Amyloid Precursor Protein

Abstract

Abundant senile plaques are a histological hallmark in the brain of Alzheimer's disease patients. Such plaques consist of, among many other constituents, aggregated beta A4 amyloid peptide. This peptide is derived from an amyloid precursor protein (APP) by irregular proteolytic processing and is considered to be involved in the development of Alzheimer's disease. To study possible interactions of brain proteins with beta A4 amyloid or other fragments of APP, beta A4 amyloid and beta A4 amyloid extended to the C-terminus of APP were recombinantly produced as fusion proteins termed "Amy" and "AmyC," respectively. Using Amy and AmyC affinity chromatography, a 35-kDa protein from rat brain was isolated that bound tightly to AmyC but not to Amy, thus indicating an interaction of the protein with the C-terminus of APP. This 35-kDa protein was identified as the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Binding of GAPDH to AmyC but not to Amy was confirmed by gel filtration. Although AmyC slightly reduced the Vmax of GAPDH, the same reduction was observed in the presence of Amy. These findings suggest that the interaction of the cytoplasmic domain of APP with GAPDH is unlikely to influence directly the rate of glycolysis but may serve another function.

Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family

“…Not only is GAPD a key enzyme in cellular energy production, but it also plays an important role in several other cellular processes, including neuronal apoptosis and neurodegenerative diseases, including AD. It is known to bind A␤ precusor protein (38) as well as A␤ (39). In several models of experimentally induced neuronal apoptosis, it is consistently observed that cell death is preceded by (i) an increase in the levels of GAPD mRNA and protein and (ii) translocation of GAPD protein from the cytoplasm to the nucleus (28,29).…”

Glyceraldehyde-3-phosphate dehydrogenase: Nuclear translocation participates in neuronal and nonneuronal cell death

“…GAPDH binds to glutamine repeats in Huntingtin and other polyglutaminecontaining proteins associated with neurodegenerative diseases (16,17). GAPDH also binds to amyloid precursor protein (18). Interestingly, polyglutamine repeats provide a ␤-pleated structure, and amyloid precursor protein also contains a ␤-pleated sheet.…”

“…Moreover, GAPDH can bind to Huntingtin, the protein whose glutamine repeats may mediate the symptoms of Huntington disease (HD) (16), as well as to the gene products with glutamine repeats involved in other neurodegenerative diseases such as spinocerebellar ataxia type-I (17), spinobulbar muscular atrophy (17), and dentatorubral pallidoluysian atrophy (16). Furthermore, GAPDH can bind to the cytoplasmic domain of amyloid precursor protein (18).…”

The Functions of the Amyloid Precursor Protein Gene and Its Derivative Peptides: II Experimental Evidence and Clinical Studies

“…APP may interact and form protein-protein complexes with the GTP binding protein G(o) [71], the enzyme glyceraldehyde-3-phosphate dehydrogenase [72]; and APOE [73]. The APOEε4 isoform was more potent than the APOEε3 isoform in compromising the neuroprotective properties of sAPP.…”