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 disease (AD) is not known. Amyloid beta peptide (A beta), a proteolytic product of the amyloid precursor protein (APP), is deposited in the senile plaques and cerebrovascular tissues of individuals with either sporadic or familial AD (FAD). Increased A beta production from mutant APPs in FAD fosters the hypothesis that overexpression of A beta plays a primary role in the pathogenesis of AD. The absence of APP mutations in sporadic AD which displays identical pathological features than FAD such as synapse and neuronal loss, senile plaques and neurofibrillary tangles, 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 undergo apoptosis by serum deprivation. Serum deprived neurons display shrunken and rounded morphology, contain condensed chromatine and fragmented DNA, which are characteristic of apoptosis. In serum deprived neurons, metabolism of APP through the nonamyloidogenic secretory pathway is decreased to 20% from 40% in control cultures whereas 4kDa A beta is increased three- to fourfold. The results suggest that human neurons undergoing apoptosis generate excess A beta and indicates a possible mechanism for increased A beta in the absence of APP mutations.
LeBlanc
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Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada.
D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000737:chemistry; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D001790:Blood Physiological Phenomena; D016895:Culture Media, Serum-Free; D005333:Fetus; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008858:Microscopy, Phase-Contrast; D008970:Molecular Weight; D009474:Neurons / Q000166:cytology / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016895:Culture Media, Serum-Free