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Anticholinergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model


Year of Publication:
Contact PI Name:
Yasumasa Yoshiyama
Contact PI Affiliation:
Laboratory for Neurodegenerative Disease Research, Clinical Research Center, Chiba East National Hospital, Japan
A. Kojima, K. Itoh, T. Uchiyama, K. Arai
Primary Reference (PubMED ID):
Funding Source:
Takeda Science Foundation
Life Science Research Foundation of Japan
Study Goal and Principal Findings:

Anticholinergics, and drugs with anticholinergic properties, are widely and frequently prescribed, especially to the elderly. It is well known that these drugs decrease cognitive function and increase the risk of dementia. Although the mechanism of anticholinergic drug-induced cognitive impairment has been assumed to be functionally reduced acetylcholine (ACh) neurotransmission, some data have indicated that anticholinergics might enhance the pathology of Alzheimer's disease. In this study, we investigated the pathological effects of anticholinergics on neurodegeneration. We chronically administered two anticholinergics, trihexyphenidyl (TP) and propiverine (PP) (the latter with less central anticholinergic action), to neurodegenerative tauopathy model mice 2 to 10 months old. Furthermore, because the ACh nervous system regulates both central and peripheral inflammation, we administered TP or PP to PS19 mice in which we had artificially induced inflammation by lipopolysaccharide injection. Tau pathology, synaptic loss, and neurodegeneration in the hippocampal region, as well as tau insolubility and phosphorylation, were markedly increased in TP-treated mice and mildly increased in PP-treated mice. Furthermore, immunohistochemical analysis revealed microglial proliferation and activation. Moreover, anticholinergics increased interleukin-1β expression in both the spleen and brain of the tauopathy model mice intraperitoneally injected with lipopolysaccharide to induce systemic inflammation. Interestingly, these alterations were more strongly observed in TP-treated mice than in PP-treated mice, consistent with the level of central anticholinergic action. Anticholinergic drugs not only impair cognitive function by decreased ACh neurotransmission, but also accelerate neurodegeneration by suppressing an ACh-dependent anti-inflammatory system. Anticholinergics should be less readily prescribed to reduce the risk of dementia.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Trihexyphenidyl (TP)
Therapeutic Target:
Muscarinic Cholinergic Receptor M1
Therapy Type:
Small Molecule
Therapeutic Agent:
Propiverine (PP)
Therapeutic Target:
Muscarinic Cholinergic Receptor

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
Tau Pathology
Activated Microglia
Neuronal Loss
Hippocampal Atrophy
Synaptic Degeneration
Soluble Tau
Insoluble Tau
c-Jun N-terminal Kinase (JNK)
phospho-c-Jun N-terminal Kinase (phospho-JNK)
Glycogen Synthase Kinase 3 beta (GSK3 beta)
phospho-Glycogen Synthase Kinase 3 beta (phospho-GSK3 beta)
Cyclin-Dependent Kinase 5 (CDK5)
phospho-Cyclin-Dependent Kinase 5 (phospho-CDK5)
Extracellular Signal-Regulated Kinase (ERK)
phospho-Extracellular Signal-Regulated Kinase (phospho-ERK)
p38 Mitogen-Activated Protein Kinase (p38 MAPK)
phospho-p38 Mitogen-Activated Protein Kinase (phospho-p38 MAPK)
Total Tau Protein
Ionized Calcium Binding Adaptor Molecule 1 (Iba1)
Interleukin 1 beta (IL-1 beta)