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-β peptides (Aβ) 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 Aβ homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Aβ or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Aβ burden in AβPPPS1, hAβPPSL, and AβPP/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 Aβ peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Aβ in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Aβ in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Aβ peptide in pre-plaque mhAβPP/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 Aβ peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Aβ transport across the Blood Brain Brain (BBB). Thus increased Aβ clearance through the BBB may contribute to reduced Aβ burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects.
AC Immune SA, Lausanne, Switzerland.
Paolo
P
Paganetti
Katia
K
Antoniello
Kavi
K
Devraj
Nicolas
N
Toni
Dairin
D
Kieran
Rime
R
Madani
Maria
M
Pihlgren
Oskar
O
Adolfsson
Wolfgang
W
Froestl
André
A
Schrattenholz
Stefan
S
Liebner
Daniel
D
Havas
Manfred
M
Windisch
John R
JR
Cirrito
Andrea
A
Pfeifer
Andreas
A
Muhs
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018727:Muscarinic Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D010641:Phenotype; D010890:Pirenzepine / Q000494:pharmacology / Q000627:therapeutic use; D011976:Receptors, Muscarinic / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D010890:Pirenzepine
Aβ brain efflux; Aβ clearance; Aβ homeostasis; AβPP transgenic mice; amyloid-β peptides; drug treatment; muscarinic receptors; plaque deposition