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.

The formation and accumulation of toxic amyloid-beta peptides (A beta) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating A beta homeostasis. Examples are the inhibition of production, misfolding, and accumulation of A beta or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain A beta burden in A beta PPPS1, hA beta PPSL, and A beta PP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced A beta peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected A beta in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected A beta in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial A beta peptide in pre-plaque mhA beta PP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of A beta peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in A beta transport across the Blood Brain Brain (BBB). Thus increased A beta clearance through the BBB may contribute to reduced A beta burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects.