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Processing of Amyloid Precursor Protein in Human Primary Neuron and Astrocyte Cultures
Author(s) -
LeBlanc Andréa C.,
Papadopoulos Maria,
Bélair Caroline,
Chu William,
Crosato Milena,
Powell Jaqueline,
Goodyer Cynthia G.
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.68031183.x
Subject(s) - microglia , senile plaques , amyloid precursor protein , astrocyte , alzheimer's disease , amyloid (mycology) , p3 peptide , neuron , secretion , biology , neuroscience , human brain , protein precursor , microbiology and biotechnology , biochemistry , pathology , central nervous system , disease , gene , immunology , medicine , inflammation , botany
Increased production of amyloid β peptide (Aβ) is highly suspected to play a major role in Alzheimer's disease (AD) pathogenesis. Because Aβ deposits in AD senile plaques appear uniquely in the brain and are fairly restricted to humans, we assessed amyloid precursor protein (APP) metabolism in primary cultures of the cell types associated with AD senile plaques: neurons, astrocytes, and microglia. We find that neurons secrete 40% of newly synthesized APP, whereas glia secrete only 10%. Neuronal and astrocytic APP processing generates five C‐terminal fragments similar to those observed in human adult brain, of which the most amyloidogenic higher‐molecular‐weight fragments are more abundant. The level of amyloidogenic 4‐kDa Aβ exceeds that of nonamyloidogenic 3‐kDa Aβ in both neurons and astrocytes. In contrast, microglia make more of the smallest C‐terminal fragment and no detectable Aβ. We conclude that human neurons and astrocytes generate higher levels of amyloidogenic fragments than microglia and favor amyloidogenic processing compared with previously studied culture systems. Therefore, we propose that the higher amyloidogenic processing of APP in neurons and astrocytes, combined with the extended lifespan of individuals, likely promotes AD pathology in aging humans.