| Summary: | Abstract Background Post-stroke dementia (PSD) is one of the major consequences after stroke. Chronic cerebral hypoperfusion (CCH) can induce vascular cognitive impairment and potentiate amyloid pathology. We investigated how CCH contributes to the development of PSD after stroke in the context of neuroinflammation and amyloid pathology. Methods We designed a unique animal model for PSD. We performed middle cerebral artery occlusion (MCAO) surgery in rats mimicking acute territorial infarct, which was followed by bilateral common carotid artery occlusion (BCCAo) surgery mimicking CCH. We performed behavioral tests including neurologic function test and water maze task and histological investigations including neuroinflammation, neuronal cell death, amyloid pathology, and aquaporin 4 (AQP4) distribution. Results Spatial memory was synergistically impaired when BCCAo was superimposed on MCAO. Neuroinflammation with astroglial or microglial activation and amyloid pathology were enhanced in the ipsilateral cortex, thalamus, and hippocampus when BCCAo was superimposed on MCAO. Glymphatic pathway-related AQP4 distribution changed from perivascular to parenchymal pattern. Conclusions Our experimental results suggest that CCH may contribute to the development of PSD by interfering with amyloid clearance through the glymphatic pathway and concomitant neuroinflammation. Therapeutic strategy to clear brain metabolic waste through the glymphatic pathway may be a promising approach to prevent PSD after stroke.
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