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 (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.
- Received March 11, 2011.
- Accepted March 31, 2011.
- © 2011 American Heart Association, Inc.