Restoring neurovascular coupling in Alzheimer's disease tauopathy through M1 mAChR modulation

Alzheimer's disease is marked by cognitive decline and early cerebrovascular dysfunction, including a reduction in neurovascular coupling (NVC) and cerebral blood flow (CBF). The accumulation of tau protein is a primary contributor to these issues, but there are few treatments that specifically target tau-induced neurovascular dysfunction.

The M1 muscarinic acetylcholine receptor (M1 mAChR) shows promise as a therapeutic target due to its importance in cognitive function. Previous studies have shown that activating M1 mAChR can improve cognitive function and neuronal survival in Alzheimer's disease mouse models, although it is unclear if this approach can restore tau-induced NVC deficits.

Researchers used P301S mice, a model of tauopathy, to investigate this question. They assessed cognitive function with the novel object recognition and Morris water maze tests, and NVC using laser speckle contrast imaging to measure changes in CBF in response to whisker stimulation. In these P301S tau mice, memory and recognition abilities were impaired, and their response to whisker stimulation was reduced, indicating an impaired NVC response.

However, when treated with VU0486846, an M1 mAChR positive allosteric modulator, this impaired NVC response was reversed. This effect was more pronounced in female mice compared to males, indicating a potential sex-biased response to M1 mAChR modulation.

These findings suggest that activating the M1 mAChR could be a promising strategy for modifying Alzheimer's disease by reversing tau-induced neurovascular dysfunction. The observation that females showed earlier improvement highlights the influence of biological sex on therapeutic efficacy.