Increased efflux of amyloid-β peptides through the blood-brain barrier by muscarinic acetylcholine receptor inhibition reduces pathological phenotypes in mouse models of brain amyloidosis.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and in vitro laboratory study without human data.
PubMed 24072071 · doi:10.3233/JAD-131091
What was done
Researchers evaluated the effect of oral administration of ACI-91 (pirenzepine), a muscarinic acetylcholine receptor inhibitor, on amyloid-β (Aβ) clearance and pathology in multiple transgenic mouse models of brain amyloidosis (AβPPPS1, hAβPPSL, AβPP/PS1, and mhAβPP/PS1d). They measured brain Aβ burden, clearance rates of intrathecally or brain-injected Aβ, urinary excretion, and interstitial Aβ peptide half-life after single-dose or 1-month treatment. In vitro experiments in differentiated endothelial monolayers assessed active Aβ transport and endothelial gene expression changes using ACI-91 and darifenacin.
What was found
Oral ACI-91 dose-dependently reduced brain Aβ burden in AβPPPS1, hAβPPSL, and AβPP/PS1 mice. One month of treatment accelerated clearance of intrathecally injected Aβ in plaque-bearing mice and promoted peripheral elimination via urinary excretion. A single dose reduced the half-life of interstitial Aβ in pre-plaque mhAβPP/PS1d mice. In vitro, muscarinic inhibition with ACI-91 and darifenacin increased active Aβ transport and altered endothelial expression of genes involved in blood-brain barrier Aβ transport. The abstract does not report specific numerical values or effect sizes.
Why it matters
This work identifies endothelial muscarinic acetylcholine receptor inhibition as a potential mechanism to promote blood-brain barrier clearance of Aβ, offering a potential strategy to reduce amyloid burden while minimizing central cholinergic side effects.
Limits
Findings are limited to animal models and in vitro cell culture; findings cannot be assumed to translate to human clinical efficacy or safety. The abstract does not disclose sample sizes (n), exact quantitative values, or statistical significance metrics.
Cited by
- supports Pirenzepine does not cross into the central nervous system.