TY - JOUR
T1 - Loss of muscarinic M1 receptor exacerbates Alzheimer's disease-like pathology and cognitive decline
AU - Medeiros, Rodrigo
AU - Kitazawa, Masashi
AU - Caccamo, Antonella
AU - Baglietto-Vargas, David
AU - Estrada-Hernandez, Tatiana
AU - Cribbs, David H.
AU - Fisher, Avraham
AU - Laferla, Frank M.
N1 - Funding Information:
Supported by grants from the NIH (NIH/NIAMS K99AR054695 to M.K.; NIH/NIA R01AG20335 and Program Project AG00538 to F.M.L.).
PY - 2011/8
Y1 - 2011/8
N2 - Alzheimer's disease (AD) is pathologically characterized by tau-laden neurofibrillary tangles and β-amyloid deposits. Dysregulation of cholinergic neurotransmission has been implicated in AD pathogenesis, contributing to the associated memory impairments; yet, the exact mechanisms remain to be defined. Activating the muscarinic acetylcholine M1 receptors (M1Rs) reduces AD-like pathological features and enhances cognition in AD transgenic models. To elucidate the molecular mechanisms by which M1Rs affect AD pathophysiological features, we crossed the 3xTgAD and transgenic mice expressing human Swedish, Dutch, and Iowa triple-mutant amyloid precursor protein (Tg-SwDI), two widely used animal models, with the M1R-/- mice. Our data show that M 1R deletion in the 3xTgAD and Tg-SwDI mice exacerbates the cognitive impairment through mechanisms dependent on the transcriptional dysregulation of genes required for memory and through acceleration of AD-related synaptotoxicity. Ablating the M1R increased plaque and tangle levels in the brains of 3xTgAD mice and elevated cerebrovascular deposition of fibrillar Aβ in Tg-SwDI mice. Notably, tau hyperphosphorylation and potentiation of amyloidogenic processing in the mice with AD lacking M 1R were attributed to changes in the glycogen synthase kinase 3β and protein kinase C activities. Finally, deleting the M1R increased the astrocytic and microglial response associated with Aβ plaques. Our data highlight the significant role that disrupting the M1R plays in exacerbating AD-related cognitive decline and pathological features and provide critical preclinical evidence to justify further development and evaluation of selective M1R agonists for treating AD.
AB - Alzheimer's disease (AD) is pathologically characterized by tau-laden neurofibrillary tangles and β-amyloid deposits. Dysregulation of cholinergic neurotransmission has been implicated in AD pathogenesis, contributing to the associated memory impairments; yet, the exact mechanisms remain to be defined. Activating the muscarinic acetylcholine M1 receptors (M1Rs) reduces AD-like pathological features and enhances cognition in AD transgenic models. To elucidate the molecular mechanisms by which M1Rs affect AD pathophysiological features, we crossed the 3xTgAD and transgenic mice expressing human Swedish, Dutch, and Iowa triple-mutant amyloid precursor protein (Tg-SwDI), two widely used animal models, with the M1R-/- mice. Our data show that M 1R deletion in the 3xTgAD and Tg-SwDI mice exacerbates the cognitive impairment through mechanisms dependent on the transcriptional dysregulation of genes required for memory and through acceleration of AD-related synaptotoxicity. Ablating the M1R increased plaque and tangle levels in the brains of 3xTgAD mice and elevated cerebrovascular deposition of fibrillar Aβ in Tg-SwDI mice. Notably, tau hyperphosphorylation and potentiation of amyloidogenic processing in the mice with AD lacking M 1R were attributed to changes in the glycogen synthase kinase 3β and protein kinase C activities. Finally, deleting the M1R increased the astrocytic and microglial response associated with Aβ plaques. Our data highlight the significant role that disrupting the M1R plays in exacerbating AD-related cognitive decline and pathological features and provide critical preclinical evidence to justify further development and evaluation of selective M1R agonists for treating AD.
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U2 - 10.1016/j.ajpath.2011.04.041
DO - 10.1016/j.ajpath.2011.04.041
M3 - Article
C2 - 21704011
AN - SCOPUS:80052479573
SN - 0002-9440
VL - 179
SP - 980
EP - 991
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 2
ER -