Skip to main content
U.S. flag

An official website of the United States government

Anti-inflammatory action of donepezil ameliorates tau pathology, synaptic loss, and neurodegeneration in a tauopathy mouse model


Year of Publication:
Contact PI Name:
Yasumasa Yoshiyama
Contact PI Affiliation:
Laboratory for Neurodegenerative Disorder Research, Clinical Research Center, Chiba East National Hospital, Chiba, Japan
Kojima Ayako, Ishikawa Chieko, Arai Kimihito
Primary Reference (PubMED ID):
Funding Source:
Takeda Science Foundation
Study Goal and Principal Findings:

Four acetylcholinesterase inhibitors (AChEIs), tacrine, donepezil (DZ), galantamine, and rivastigmine have been available for long-term clinical use to compensate for ACh dysfunction in the brain. An increasing amount of evidence has revealed improved or stabilized cognitive decline, as well as behavioral and psychological symptoms with AChEIs. Although the symptomatic efficacy of AChEIs is assumed to take place through augmentation of ACh-mediated neurotransmission, clinical observations suggest  that AChEI-action mechanisms other than enhanced cholinergic neurotransmission, also exist. For example,in vitro and animal studies utilizing AChEIs have shown reduced cell death induced by exogenous cytotoxins, including amyloid- β, glutamate, okadaic acid, and carbon monoxide gas. In addition, ACh has recently been shown to provide anti-inflammatory functions, suggesting that AChEIs influence neurodegeneration through anti-inflammatory effects. In this study, DZ, which is the most widely used AChEI for AD treatment, was administrated to PS19 mice for an extended period of time (8 months), followed by histopathological and biochemical analysis that focused on tau pathology, neurodegeneration, and inflammatory processes.  Treatment with DZ resulted in amelioration of neuroinflammation, tau pathology, synaptic loss, glial activation and neuronal loss, as well as decreased tau insolubility and phosphorylation. It appeared that DZ ameliorated tau phosphorylation via JNK suppression. The authors concluded that ACh did not act just as a cognition-linking neurotransmitter, but suppressed pathological mechanisms of neurodegeneration via anti-inflammatory action.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Neuronal Loss
GSK3 beta/phospho-GSK3 beta
Activated Astrocytes
Activated Microglia
Interleukin 1 beta (IL-1 beta)
Cyclooxygenase 2 (COX2)