Ray_2020_Transl.Psychiatry_10_47

Rivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer's disease (AD). Amyloid-beta peptide (Abeta) generated from its precursor protein (APP) by beta-secretase (or BACE1) and gamma-secretase endoproteolysis. Alternative APP cleavage by alpha-secretase (a family of membrane-bound metalloproteases- Adamalysins) precludes the generation of toxic Abeta and yields a neuroprotective and neurotrophic secreted sAPPalpha fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate alpha-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards alpha-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the alpha-secretase inhibitor TAPI and assayed for levels of APP processing products and alpha-secretases. We subsequently treated 3xTg (transgenic) mice with rivastigmine and harvested hippocampi to assay for levels of APP processing products. We also assayed postmortem human control, AD, and AD brains from subjects treated with rivastigmine for levels of APP metabolites. Rivastigmine dose-dependently promoted alpha-secretase activity by upregulating levels of ADAM-9, -10, and -17 alpha-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPPalpha elevation. Rivastigmine treatment elevated levels of sAPPalpha in 3xTg mice. Consistent with these results, we also found elevated sAPPalpha in postmortem brain samples from AD patients treated with rivastigmine. Rivastigmine can modify the levels of several shedding proteins and directs APP processing toward the non-amyloidogenic pathway. This novel property of rivastigmine can be therapeutically exploited for disease-modifying intervention that goes beyond symptomatic treatment for AD.