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Tau pathology and neurochemical changes associated with memory dysfunction in an optimised murine model of global cerebral ischaemia - a potential model for vascular dementia?

Research output: Contribution to journalArticle

  • Sabah Khan
  • Nadira Yuldasheva
  • Trevor FC Batten
  • Alasdair Pickles
  • Katherine A B Kellett
  • Sikha Saha
Original languageEnglish
Pages (from-to)134-144
Number of pages11
JournalNeurochemistry International
Volume118
Early online date10 Apr 2018
DOIs
StatePublished - 1 Sep 2018
Cerebral ischemia is known to be a major cause of death and the later development of Alzheimer’s disease and vascular dementia. However, ischemia induced cellular damage that initiates these diseases remain poorly understood. This is primarily due to lack of clinically relevant models that are highly reproducible. Here, we have optimised a murine model of global cerebral ischaemia with multiple markers to determine brain pathology, neurochemistry and correlated memory deficits in these animals. Cerebral ischaemia in mice was induced by bilateral common carotid artery occlusion. Following reperfusion, the mice were either fixed with 4% paraformaldehyde or decapitated under anaesthesia. Brains were processed for Western blotting or immunohistochemistry for glial (GLT1) and vesicular (VGluT1, VGluT2) glutamate transporters and paired helical filament (PHF1) tau. The PHF1 tau is the main component of neurofibrillary tangle, which is the pathological hallmarks of Alzheimer’s disease and vascular dementia. The novel object recognition behavioural assay was used to investigate the functional cognitive consequences in these mice. The results show consistent and selective neuronal and glial cell changes in the hippocampus and the cortex together with a significant reduction in GLT1 (***P< 0.001), VGluT1 (**P<0.01) and VGluT2 (***P<0.001) expression in the hippocampus in occluded mice as compared to sham-operated animals. These changes are associated with increased PHF1 (***P<0.0001) protein and a significant impairment of performance (*p<0.0006, N=6/group) in the novel object recognition test. This model represents a useful tool for investigating cellular, biochemical and molecular mechanisms of global cerebral ischaemia and may be an ideal preclinical model for vascular dementia. Keywords Global

    Research areas

  • Global cerebral ischaemia, Glutamate Transporter, Tau protein, Memory deficit, Vascular dementia, Stroke

Related faculties, schools or groups

External organisations

  • Leeds University School of Medicine
  • Leeds University Faculty of Biological Sciences
  • University of Manchester Division of Neuroscience & Experimental Psychology
  • Leeds University Division of Cardiovascular & Diabetes Research

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