INCREASED PRODUCTION OF 4 KDA AMYLOID-BETA PEPTIDE IN SERUM-DEPRIVED HUMAN PRIMARY NEURON CULTURES - POSSIBLE INVOLVEMENT OF APOPTOSIS

The etiology of the amyloid beta peptide in sporadic Alzheimer's disea se (AD) is not known. Amyloid beta peptide (A beta), a proteolytic pro duct of the amyloid precursor protein (APP), is deposited in the senil e plaques and cerebrovascular tissues of individuals with either spora dic or familial AD (FAD). Increased A beta production from mutant APPs in FAD fosters the hypothesis that overexpression of A beta plays a p rimary role in the pathogenesis of AD. The absence of APP mutations in sporadic AD which displays identical pathological features than FAD s uch as synapse and neuronal loss, senile plaques and neurofibrillary t angles, suggests other causes for overexpression and/or deposition of A beta. To investigate the effect of neuronal death on APP metabolism and A beta secretion, human primary neuron cultures were induced to un dergo apoptosis by serum deprivation. Serum deprived neurons display s hrunken and rounded morphology, contain condensed chromatine and fragm ented DNA, which are characteristic of apoptosis. In serum deprived ne urons, metabolism of APP through the nonamyloidogenic secretory pathwa y is decreased to 20% from 40% in control cultures whereas 4kDa A beta is increased three- to fourfold. The results suggest that human neuro ns undergoing apoptosis generate excess A beta and indicates a possibl e mechanism for increased A beta in the absence of APP mutations.