title: Disease-Modifying Effects of M1Muscarinic Acetylcholine Receptor Activation in an Alzheimer's Disease Mouse Model.
abstract: Alzheimer's disease (AD) is the leading cause of dementia worldwide, and currently no disease-modifying therapy is available to slow or prevent AD, underscoring the urgent need for neuroprotective therapies. Selective M1muscarinic acetylcholine receptor (mAChR) activation is an attractive mechanism for AD therapy since M1mediates key effects on memory, cognition, and behavior and has potential for disease-modifying effects on Aβ formation and tau phosphorylation. To validate M1as a neuroprotective treatment target for AD, the M1-selective agonist, VU0364572, was chronically dosed to 5XFAD mice from a young age preceding Aβ pathology (2 months) to an age where these mice are known to display memory impairments (6 months). Chronic M1activation prevented mice from becoming memory-impaired, as measured by Morris water maze (MWM) testing at 6 months of age. Additionally, M1activation significantly reduced levels of soluble and insoluble Aβ40,42in the cortex and hippocampus of these animals, as measured by ELISA and immunohistochemistry. Moreover, soluble hippocampal Aβ42levels were strongly correlated with MWM memory impairments and M1activation with VU0364572 abolished this correlation. Finally, VU0364572 significantly decreased oligomeric (oAβ) levels in the cortex, suggesting one mechanism whereby VU0364572 may be exerting its neuroprotective effects is by reducing the available oAβ pool in the brain. These findings suggest that chronic M1activation has neuroprotective potential for preventing memory impairments and reducing neuropathology in AD. M1activation therefore represents a promising avenue for preventative treatment, as well as a promising opportunity to combine symptomatic and disease-modifying effects for early AD treatment.
authors.forename: Evan P
authors.identifier: 0000-0003-3531-4387
authors.initials: EP
authors.lastname: Lebois
authors.forename: Jason P
authors.initials: JP
authors.lastname: Schroeder
authors.affiliation: Department of Neurology, Washington University , St. Louis, Missouri 63130, United States.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Esparza
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery , Nashville, Tennessee 37067, United States.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery , Nashville, Tennessee 37067, United States.
authors.forename: Craig W
authors.identifier: 0000-0003-0168-1445
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery , Nashville, Tennessee 37067, United States.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Department of Neurology, Washington University , St. Louis, Missouri 63130, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Brody
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery , Nashville, Tennessee 37067, United States.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.affiliation: Alzheimer's Disease Research Center, Emory University , Atlanta, Georgia 30329, United States.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology; D043643:Receptor, Muscarinic M1 / Q000819:agonists / Q000187:drug effects*
chemical_list: D001549:Benzamides; D001713:Biphenyl Compounds; D018696:Neuroprotective Agents; D043643:Receptor, Muscarinic M1; C574617:VU0364572
keywords: Alzheimer’s; Muscarinic; acetylcholine; amyloid; hippocampus; memory