Effects of rivastigmine on secreted amyloid precursor protein and beta-amyloid secretion in neuroblastoma SK-N-SH cells

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive impairment of memory and cognition. The currently available pharmacological treatment of AD consists mainly of cholinesterase inhibitors. Rivastigmine is one of the cholinesterase inhibitors clinically used to treat this disease, and many clinical trials have indicated that it did alleviate some AD symptoms without causing apparent side effects. Since the amyloid precursor protein (APP) processing imbalance plays a crucial role in AD pathogenesis, the effects of rivastigmine on APP processing were investigated. In neuroblastoma SK-N-SH cells, rivastigmine significantly increased the secretion of sAPP alpha and decreased the release of A beta 40 and A beta 42 as compared with control group, but it has no effect on cellular full length APP expression. Rivastigmine significantly increased alpha-secretase activity and decreased beta-secretase activity as compared with control group. The increased sAPP alpha can be partially blocked by muscarinic receptor inhibitor scopolamine but not by nicotinic receptor antagonist alpha-Bungarotoxin. The effect of rivastigmine on sAPP alpha can be partially reversed by PKC inhibitor GF109203X, ERK inhibitor PD98059 and JNK inhibitor SP600125. The data present here indicated that rivastigmine can regulate APP processing in vitro by increasing sAPP alpha secretion and decreasing A beta release and this pharmacological property may underlie the clinical effect of the drug in the treatment of AD patients.