Alzheimer's disease (AD) is pathologically characterized by tau-laden neurofibrillary tangles and ␤-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 M 1 receptors (M 1 Rs) reduces AD-like pathological features and enhances cognition in AD transgenic models. To elucidate the molecular mechanisms by which M 1 Rs 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 M 1 R ؊/؊ mice. Our data show that M 1 R 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 M 1 R increased plaque and tangle levels in the brains of 3xTgAD mice and elevated cerebrovascular deposition of fibrillar A␤ in Tg-SwDI mice. Notably, tau hyperphosphorylation and potentiation of amyloidogenic processing in the mice with AD lacking M 1 R were attributed to changes in the glycogen synthase kinase 3␤ and protein kinase C activities. Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to cognitive impairment and dementia. The neuropathological hallmarks of AD are amyloid plaques, composed of ␤-amyloid (A␤) peptides, and neurofibrillary tangles, composed of the hyperphosphorylated tau protein. The deposition of fibrillar A␤ in the cerebrovasculature, a condition known as cerebral amyloid angiopathy (CAA), is also a prominent feature of AD. Together with associated processes, such as inflammation and oxidative stress, these pathological cascades contribute to loss of synaptic integrity and progressive neurodegeneration. 1Restoring cholinergic dysfunction has been a primary means of improving the cognitive decline in AD because four of the five Food and Drug Administration-approved drugs are acetylcholinesterase inhibitors, with the notable exception of memantine.2 Acetylcholinesterase inhibitors provide mild symptomatic relief but eventually lose efficacy over time, most likely because they are not disease-modifying agents.1 Alternatively, recent evidence 3,4 indicates that stimulation of muscarinic acetylcholine receptors, in particular the M 1 receptor (M 1 R), restores cognition and attenuates AD-like pathological features in several different animal models, rendering it an attractive therapeutic approach for AD. The M 1 R is the most abundant muscarinic acetylcholine receptor subtype in the cerebral cortex and hippocampus, the two main brain reSupported by grants from the NIH (NIH/NIAMS K99AR054695 to M.K.; NIH/NIA R01AG20335 and Program Project AG00538 to F.M.L.).

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