Dual Cognition Improving Mechanisms of Huperzine A in Vascular Dementia Mice via Neurometabolic Regulation

Vascular dementia (VaD) is a poorly treated disease that involves complicated pathology such as neuronal damage and neural circuit dysfunction. Huperzine A (HupA) is commonly used for clinical treatment of cognitive impairment, the mechanism of which is prevailingly attributed to the increase of synaptic acetylcholine (ACh) level. Here we elucidate an integral neurometabolic mechanism for HupA in the treatment of cognitive impairment in VaD. HupA effectively alleviated bilateral common carotid artery occlusion (BCCAO)-induced neuronal damage, neuroinflammation and cognitive decline in mice, accompanied by a notable restoration of ACh homeostasis in the dorsal striatum (STRd). HupA or ACh injection into the STRd recapitulated the cognitive effects, while α7nAChR antagonist blocked the neuroprotective effects in both primary neurons and VaD mice. By neural circuit mapping and functional manipulation, we further identified that HupA-induced ACh accumulation to the STRd recruits a STRdGABA→SNrGABA neural circuit to synergistically improve the cognitive network in VaD mice. Overall, we reveal a dual mechanism orchestrated by STRd ACh signaling through which HupA confers cognitive improvement in VaD mice. These findings underscore the therapeutic value of targeting neurometabolic nodes for the treatment of VaD and potentially other forms of dementia.