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Neurobiol Aging. 2014 Jul;35(7):1605-14. doi: 10.1016/j.neurobiolaging.2014.01.005. Epub 2014 Jan 8.

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

Author information

  • 1Department of Anatomy and Cell Biology, Canadian Institutes of Health Research Group on Vascular Cognitive Impairment, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada. Electronic address: zamtul@uwo.ca.
  • 2Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
  • 3Department Physiology, University of Toronto, Toronto, Ontario, Canada.
  • 4Department of Neuroscience, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada.
  • 5Department of Cellular and Physiological Sciences, The Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
  • 6Department of Laboratory Medicine and Pathobiology, St Michael's Hospital and Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Ontario, Canada.
  • 7Department of Clinical Neurological Sciences, London Health Sciences Center and University of Western Ontario, London, Ontario, Canada.
  • 8Department of Anatomy and Cell Biology, Canadian Institutes of Health Research Group on Vascular Cognitive Impairment, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

Abstract

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 β-amyloid (Aβ) toxicity in the hippocampus. Stroke was induced by unilateral striatal injection of endothelin-1, the potent vasoconstrictor. Aβ toxicity was modeled by bilateral intracerebroventricular injections of the toxic fragment Aβ. Gross morphologic changes in comorbid Aβ 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 Aβ 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 Aβ toxicity and stroke occur comorbidly but also demonstrates that this comorbid rat model exhibits physiopathology that is highly characteristic of the human condition.

Copyright © 2014 Elsevier Inc. All rights reserved.

KEYWORDS:

Axonal retraction; Fear conditioning; Neurogenesis; Stroke; β-amyloid

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