Blocking α₁ Adrenergic Receptor as a Novel Target for Treating Alzheimer's Disease

While amyloidopathy and tauopathy have been recognized as hallmarks in Alzheimer's disease (AD) brain, recently, increasing lines of evidence have supported the pathological roles of cerebrovascular changes in the pathogenesis and progression of AD. Restoring or ameliorating the impaired cerebrovascular function during the early phase of the disease may yield benefits against the cognitive decline in AD. In the present study, we evaluated the potential therapeutic effects of nicergoline [NG, a well-known α1 adrenergic receptor (ADR) blocker and vasodilator] against AD through ameliorating vascular abnormalities. Our in vitro data revealed that NG could reverse β-amyloid_1-42 (Aβ_1-42)-induced PKC/ERK1/2 activation, the downstream pathway of α1-ADR activation, in α1-ADR-overexpressed N2a cells. NG also blocked Aβ_1-42- or phenylephrine-induced constrictions in isolated rat arteries. All these in vitro data may suggest ADR-dependent impacts of Aβ on vascular function and the reversal effect of NG. In addition, the ameliorating impacts of NG treatment on cerebral vasoconstriction, vasoremodeling, and cognitive decline were investigated in vivo in a PSAPP transgenic AD mouse model. Consistent with in vitro findings, the chronic treatment of NG significantly ameliorated the cerebrovascular dysfunctions and Aβ plaque depositions in the brain. Moreover, an improved cognitive performance was also observed. Taken together, our findings supported the beneficial effects of NG on AD through adrenergic-related mechanisms and highlighted the therapeutic potential of α1-adrenergic vasomodulators against AD pathologies.