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

Abstract

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 (Aβ) 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 Aβ (Aβ toxicity) using a nonphysiological Aβ peptide (Aβ 25 to 35). The experimental animals were divided into 4 groups, including sham, single injury (Aβ toxicity or BCCAo), and combined injury (BCCAo-Aβ 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–Aβ toxicity group as compared to the BCCAo or Aβ 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–Aβ toxicity group compared to the Aβ toxicity group. Conclusion: Our experimental results support a clinical hypothesis of the deleterious interaction between chronic cerebral hypoperfusion and Aβ toxicity. Chronic cerebral hypoperfusion-induced perturbation in the equilibrium of AD-related pathology may exacerbate cognitive impairment in a rat model of combined injury.