beta-Secretase inhibitor increases amyloid-beta precursor protein level in rat brain cortical primary neurons induced by okadaic acid / 中华医学杂志(英文版)

ABSTRACT

<p><b>BACKGROUND</b>Senile plaques and neurofibrillary tangles (NFTs) represent two of the major histopathological hallmarks of Alzheimer's disease (AD). The plaques are primarily composed of aggregated amyloid beta (Abeta) peptides. The processing of amyloid-beta precursor protein (AbetaPP) in okadaic acid (OA)-induced tau phosphorylation primary neurons was studied.</p><p><b>METHODS</b>Primary cultures of rat brain cortical neurons were treated with OA and beta-secretase inhibitor. Neurons' viability was measured. AbetaPP processing was examined by immunocytochemistry and Western blotting with specific antibodies against the AbetaPP-N-terminus (NT) and AbetaPP-C-terminus (CT).</p><p><b>RESULTS</b>Ten nmol/L OA had a time-dependent suppression effect on primary neurons' viability. The suppression effect was alleviated markedly by pretreatment with beta-secretase inhibitor. After OA treatment, both AbetaPP and beta-C-terminal fragment (betaCTF) were significantly increased in neurons. AbetaPP level was increased further in neurons pretreated with beta-secretase inhibitor.</p><p><b>CONCLUSIONS</b>In OA-induced tau phosphorylation cell model, inhibition of beta-secretase may protect neurons from death induced by OA. Because of increased accumulation of AbetaPP in neurons after OA treatment, more AbetaPP turns to be cleaved by beta-secretase, producing neurotoxic betaCTF. As apotential effective therapeutic target, beta-secretase is worth investigating further.</p>