Paganetti_2014_J.Alzheimers.Dis_38_767

The formation and accumulation of toxic amyloid-beta peptides (Abeta) 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 Abeta homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Abeta or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Abeta burden in AbetaPPPS1, hAbetaPPSL, and AbetaPP/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 Abeta peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Abeta in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Abeta in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Abeta peptide in pre-plaque mhAbetaPP/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 Abeta peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Abeta transport across the Blood Brain Brain (BBB). Thus increased Abeta clearance through the BBB may contribute to reduced Abeta burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects.