Comorbid Aβ toxicity and stroke: hippocampal atrophy, pathology, and cognitive deficit

Numerous clinical and epidemiological reports indicate that patients with history of vascular illness such as stroke are more likely to develop dementia as the clinical manifestation of Alzheimer's disease. However, there are little data regarding the pathologic mechanisms that link vascular risk factors to the factors associated with dementia onset. We provide evidence that suggests intriguing detrimental interactions between stroke and beta-amyloid (A beta) toxicity in the hippocampus. Stroke was induced by unilateral striatal injection of endothelin-1, the potent vasoconstrictor. A beta toxicity was modeled by bilateral intracerebroventricular injections of the toxic fragment A beta. Gross morphologic changes in comorbid A beta and stroke rats were enlargement of the lateral ventricles with concomitant shrinkage of the hippocampus. The hippocampus displayed a series of synergistic biochemical alterations, including microgliosis, deposition of A beta precursor protein fragments, and cellular degeneration. In addition, there was bilateral induction of connexin43, reduced neuronal survival, and impaired dendritic development of adult-born immature neurons in the dentate gyrus of these rats compared with either rats alone. Behaviorally, there was impairment in the hippocampal-based discriminative fear-conditioning to context task indicating learning and memory deficit. These results suggest an insight into the relationship between hippocampal atrophy, pathology, and functional impairment. Our work not only highlights the exacerbated pathology that emerges when A beta toxicity and stroke occur comorbidly but also demonstrates that this comorbid rat model exhibits physiopathology that is highly characteristic of the human condition. (C) 2014 Elsevier Inc. All rights reserved.