title: Anti-inflammatory action of donepezil ameliorates tau pathology, synaptic loss, and neurodegeneration in a tauopathy mouse model.
abstract: Acetylcholinesterase inhibitors (AChEIs) are widely used to compensate for acetylcholine (ACh) depletion in the Alzheimer's disease (AD) brain. Some clinical and experimental studies, however, have suggested that AChEIs also provide neuroprotection. To assess the effect of AChEIs on neurodegeneration, donepezil (DZ), an AChEI, was administered to FTDP-17 model mice with a P301S tau mutation (line PS19). Eight months of DZ treatment resulted in amelioration of neuroinflammation, tau pathology, synaptic loss, and neuronal loss, as well as decreased tau insolubility and phosphorylation. Tau kinase activity analysis demonstrated significantly suppressed c-Jun N-terminal kinase (JNK) in the brains of DZ-treated PS19 mice. Recently, ACh has been shown to suppress inflammation, which plays a role in neurodegeneration. To confirm the anti-inflammatory effect of DZ, PS19 mice were injected with lipopolysaccharide, in combination with or without DZ, for one month. Results demonstrated that DZ suppressed IL-1β and COX-2 expression in the brain, as well as the spleen, suggesting that DZ directly prevents systemic inflammation. These data indicated that ACh did not act just as a cognition-linking neurotransmitter, but might suppress pathological mechanisms of neurodegeneration via anti-inflammatory action.
authors.affiliation: Laboratory for Neurodegenerative Disorder Research, Clinical Research Center, Chiba East National Hospital, Chiba, Japan. neuroyy@cehpnet.com
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Yoshiyama
authors.forename: Ayako
authors.initials: A
authors.lastname: Kojima
authors.forename: Chieko
authors.initials: C
authors.lastname: Ishikawa
authors.forename: Kimihito
authors.initials: K
authors.lastname: Arai
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D000077265:Donepezil; D006801:Humans; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D013569:Synapses / Q000187:drug effects / Q000473:pathology*; D024801:Tauopathies / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016875:tau Proteins / Q000235:genetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007189:Indans; D010880:Piperidines; D016875:tau Proteins; D000077265:Donepezil