TY - JOUR
T1 - Tau pathology and neurochemical changes associated with memory dysfunction in an optimised murine model of global cerebral ischaemia - a potential model for vascular dementia?
AU - Khan, Sabah
AU - Yuldasheva, Nadira
AU - Batten, Trevor FC
AU - Pickles, Alasdair
AU - Kellett, Katherine A B
AU - Saha, Sikha
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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
AB - 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
KW - Global cerebral ischaemia
KW - Glutamate Transporter
KW - Tau protein
KW - Memory deficit
KW - Vascular dementia
KW - Stroke
UR - http://eprints.whiterose.ac.uk/129758/
U2 - 10.1016/j.neuint.2018.04.004
DO - 10.1016/j.neuint.2018.04.004
M3 - Article
SN - 0197-0186
VL - 118
SP - 134
EP - 144
JO - Neurochemistry International
JF - Neurochemistry International
ER -