Synergistic Memory Impairment Through the Interaction of Chronic Cerebral Hypoperfusion and Amlyloid Toxicity in a Rat Model

Background and Purpose-Vascular pathology and Alzheimer disease (AD) pathology have been shown to coexist in the brains of dementia patients. We investigated how cognitive impairment could be exacerbated in a rat model of combined injury through the interaction of chronic cerebral hypoperfusion and amyloid beta (A beta) toxicity. Methods-In Wistar rats, chronic cerebral hypoperfusion was modeled by permanent occlusion of bilateral common carotid arteries (BCCAo). Further, AD pathology was modeled by bilateral intracerebroventricular A beta (A beta toxicity) using a nonphysiological A beta peptide (A beta 25 to 35). The experimental animals were divided into 4 groups, including sham, single injury (A beta toxicity or BCCAo), and combined injury (BCCAo-A beta toxicity) groups (n=7 per group). Cerebral blood flow and metabolism were measured using small animal positron emission tomography. A Morris water maze task, novel object location and recognition tests, and histological investigation, including neuronal cell death, apoptosis, neuroinflammation, and AD-related pathology, were performed. Results-Spatial memory impairment was synergistically exacerbated in the BCCAo-A beta toxicity group as compared to the BCCAo or A beta toxicity groups (P<0.05). Compared to the sham group, neuroinflammation with microglial or astroglial activation was increased both in multiple white matter lesions and the hippocampus in other experimental groups. AD-related pathology was enhanced in the BCCAo-A beta toxicity group compared to the A beta toxicity group. Conclusion-Our experimental results support a clinical hypothesis of the deleterious interaction between chronic cerebral hypoperfusion and A beta toxicity. Chronic cerebral hypoperfusion-induced perturbation in the equilibrium of AD-related pathology may exacerbate cognitive impairment in a rat model of combined injury. (Stroke. 2011;42:2595-2604.)