Abstract
Rivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer’s disease (AD). Amyloid-β peptide (Aβ) generated from its precursor protein (APP) by β-secretase (or BACE1) and γ-secretase endoproteolysis. Alternative APP cleavage by α-secretase (a family of membrane-bound metalloproteases– Adamalysins) precludes the generation of toxic Aβ and yields a neuroprotective and neurotrophic secreted sAPPα fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate α-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards α-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the α-secretase inhibitor TAPI and assayed for levels of APP processing products and α-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 α-secretase activity by upregulating levels of ADAM-9, -10, and -17 α-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPPα elevation. Rivastigmine treatment elevated levels of sAPPα in 3×Tg mice. Consistent with these results, we also found elevated sAPPα 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.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia and the fifth leading cause of death in the elderly[1]
We concluded that the apparent elevation of sAPPα was not likely to be solely due to overall increases in culture cell number
We had previously determined that rivastigmine treatment of primary rat brain cell cultures (PRBC) substantially preserved neuronal structure and protected neurons from degeneration while maintaining levels of neuronally-originated APP forms[17]
Summary
Alzheimer’s disease (AD) is the most common cause of dementia and the fifth leading cause of death in the elderly[1]. To generate Aβ, a type 1 integral membrane protein, APP, is sequentially cleaved by β-secretase 1. (BACE1) into two fragments: secreted APPβ (sAPPβ) and a membrane-bound cytoplasmic tail fragment β (CTFβ) of 99 amino acids, which is further processed by γ-secretase, a complex of four integral membrane subunits. Aβ secreted from cultured cells varies in length from 36 to 43 amino acids). Aβ is normally secreted into cell culture media, cerebrospinal fluid, plasma and the vitreous humor[6], but it represents a minor fraction of peptides derived from γ-secretase cleavage of APP. The majority of APP is processed by α-secretase at a site within the Aβ peptide sequence to a longer secreted APPα (sAPPα) and CTFα (83 amino acids), which is further
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