Early cerebral hypoperfusion promotes spatially biased tau pathology in tau-seeded PS19 mice

Growing evidence has demonstrated a significant association between reduced cerebral blood flow and Alzheimer's disease (AD)-related cognitive impairment. Chronic cerebral hypoperfusion (CCH) has been reported to exacerbate tau hyperphosphorylation and behavioral deficits in rodents, but whether CCH promotes tau pathology at the initial stage of tauopathy remains unclear. Here we show, using a tau-seeded PS19 mouse model with unilateral common carotid artery occlusion, that early CCH exacerbates spatially biased tau pathology, inducing ipsilateral enrichment of insoluble tau in the hippocampus and, in the cortex, an ipsilateral increase that was dependent on the presence of tau seeds. Early CCH also induces myelin loss in the cortex and dorsal fornix, although no synergistic interaction was detected between tau seeds and CCH. Additionally, early CCH promotes microglial activation and IL-1β elevation, and increases hippocampal neuronal loss. In the Morris water maze, early CCH-exposed mice display a marginal trend toward reduced spatial memory performance that did not reach statistical significance. These findings indicate that early CCH facilitates tau pathology and neuroinflammation at the early stage of tauopathy, with only a marginal trend toward early cognitive changes, providing experimental evidence that vascular hypoperfusion may act as a disease modifier in the initial phase of tau pathology, with potential implications for early detection and therapeutic targeting of vascular contributions to tauopathies.