Donepezil Reduces Amyloid Precursor Protein Endocytosis by Resulting from Increase in the Expression of Sorting Nexin Protein 33

Donepezil, the most widely used drug for treatment of Alzheimer's disease (AD), is an acetylcholinesterase (AChE) inhibitor and thought to improve cognition by stimulating cholinergic neurotransmission. However, no correlation has yet been established between inhibitory role AChE inhibitors their therapeutic effects when in AD patients. The cleavage pathway amyloid precursor protein (APP) includes amyloidgenic (β, γ-cleavage) non-amyloidgenic (α-cleavage) pathways. intracellular transportation APP important determining these It suggested that sorting nexin (SNX) family proteins regulates transport APP, thereby enhancing α-cleavage. In this study, we examined donepezil on SNX33 expression changes processing primary cultures fetal rat cortical neurons. While increased levels soluble APPα (sAPPα) culture media, were observed regarding full-length cell lysate. Donepezil also reduced release β (Aβ) into media a concentration- time-dependent manner. This reduction was not affected acetylcholine receptor antagonists. membrane surface elevated donepezil. Furthermore, SNX knockdown antisense morpholino oligos prevented These results indicated at plasma decreasing endocytosis through upregulation SNX33, suggesting might stimulate non-amyloidogenic pathway. new mechanism action currently anti-AD may provide valuable basis future discovery.