beta-Secretase inhibitor increases amyloid-beta precursor protein level in rat brain cortical primary neurons induced by okadaic acid.
BACKGROUND
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Yu
Chun-Jiang
CJ
Department of Neurology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
Wang
Wei-Zhi
WZ
Liu
Wei
W
D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016564:Amyloid beta-Protein Precursor / Q000032:analysis*; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D019319:Okadaic Acid / Q000494:pharmacology*; D010446:Peptide Fragments / Q000032:analysis; D051381:Rats
D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D019319:Okadaic Acid; D053829:Amyloid Precursor Protein Secretases