Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease
| Autor: | Nigel H. Greig, Balmiki Ray, Peter T. Nelson, Hanuma Kumar Karnati, Kumar Sambamurti, Bryan Maloney, Debomoy K. Lahiri |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Transgene Rivastigmine Diseases Pharmacology Neuroprotection Article lcsh:RC321-571 Amyloid beta-Protein Precursor Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Alzheimer Disease Prohibitins mental disorders medicine Animals Aspartic Acid Endopeptidases Humans lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Biological Psychiatry Protein kinase C Cholinesterase Amyloid beta-Peptides biology Chemistry Correction Health sciences Human brain Rats 3. Good health Psychiatry and Mental health 030104 developmental biology medicine.anatomical_structure biology.protein Amyloid Precursor Protein Secretases Signal transduction Psychiatric disorders 030217 neurology & neurosurgery Neurotrophin medicine.drug |
| Zdroj: | Translational Psychiatry Translational Psychiatry, Vol 10, Iss 1, Pp 1-17 (2020) |
| ISSN: | 2158-3188 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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