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Rivastigmine modifies the ?-secretase pathway and potentially early Alzheimer's disease.

ABSTRACT: Rivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer's disease (AD). Amyloid-? peptide (A?) generated from its precursor protein (APP) by ?-secretase (or BACE1) and ?-secretase endoproteolysis. Alternative APP cleavage by ?-secretase (a family of membrane-bound metalloproteases- Adamalysins) precludes the generation of toxic A? and yields a neuroprotective and neurotrophic secreted sAPP? fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate ?-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards ?-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the ?-secretase inhibitor TAPI and assayed for levels of APP processing products and ?-secretases. We subsequently treated 3×Tg (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 ?-secretase activity by upregulating levels of ADAM-9, -10, and -17 ?-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPP? elevation. Rivastigmine treatment elevated levels of sAPP? in 3×Tg mice. Consistent with these results, we also found elevated sAPP? 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.


PROVIDER: S-EPMC7026402 | BioStudies | 2020-01-01

REPOSITORIES: biostudies

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