PAR-1 in Alzheimer's Disease: Pathophysiological Insights and Mechanistic Perspectives.

The G protein-coupled receptor (GPCR) known as protease-activated receptor-1 (PAR-1) is triggered by thrombin and plays a multifaceted role in the onset and progression of Alzheimer's disease (AD). AD is an irreversible neurodegenerative disease characterized by amyloid-β (Aβ) accumulation, neuroinflammation, tau hyperphosphorylation, and synaptic dysfunction. Thrombin activates PAR-1, which plays multiple roles in the brain. It exacerbates neuroinflammation and Aβ pathology but also protects synaptic plasticity. In a preclinical model, PAR-1 inhibition rescues cognitive deficits and decreases Aβ accumulation, suggesting therapeutic potential. However, PAR-1 activation promotes Tau hyperphosphorylation and neurofibrillary tangle formation, contributing to synaptic loss and cognitive decline. PAR-1 increases the permeability of the blood‒brain barrier (BBB), facilitating the entry of toxic substances into the brain and increasing neurodegeneration. Although strong preclinical evidence exists, no clinical trials have yet directly targeted PAR-1 in AD. This review summarizes current understanding of the PAR-1 mechanism in AD and highlights its roles in Aβ deposition, neuroinflammation, and tau pathology. It also discusses the challenges and opportunities for translating PAR-1 modulation into clinical therapies, including repurposing existing PAR-1 inhibitors. By addressing the dual role of PAR-1 function, researchers may develop novel multitarget strategies to combat the multifactorial pathophysiology of AD.