Disease-Modifying Effects of M1 Muscarinic Acetylcholine Receptor Activation in an Alzheimer's Disease Mouse Model

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 M₁ Muscarinic Acetylcholine Receptor (mAChR) activation is an attractive mechanism for AD therapy since M₁ mediates key effects on memory, cognition, and behavior and has potential for disease-modifying effects on Aβ formation and tau phosphorylation. To validate M₁ as 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 M₁ activation prevented mice from becoming memory-impaired, as measured by Morris water maze (MWM) testing at 6 months of age. Additionally, M₁ activation significantly reduced levels of soluble and insoluble Aβ_40,42 in the cortex and hippocampus of these Animals, as measured by ELISA and immunohistochemistry. Moreover, soluble hippocampal Aβ₄₂ levels were strongly correlated with MWM memory impairments and M₁ activation 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 M₁ activation has neuroprotective potential for preventing memory impairments and reducing neuropathology in AD. M₁ activation 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.

Alzheimer’s; Muscarinic; acetylcholine; amyloid; hippocampus; memory.