María La Calle Aurioles, , McGill University
Supervisor: Edith Hamel, Montreal Neurological Institute
We aim to develop and validate a mouse model of combined cerebrovascular disease and diabetes (DB) to investigate the interplay between impaired cerebrovascular function and hyperglycemia in cognitive failure. We will induce DB in transgenic mice for transforming growth factor-B1 (TGF mice). TGF mice display a cerebrovascular pathology (vascular fibrosis, remodeling and string vessel pathology) that results in impaired dilatory function, cerebral hypoperfusion and neurovascular uncoupling, similar to what can be found in vascular dementia (VD) and Alzheimer’s disease (AD). However, TGF mice do not show cognitive impairment despite subtle, not significant, reduction in their performance in old age. We hypothesize that TGF+DB mice will show earlier or more severe cognitive impairment than mice with DB alone due to the additional deleterious effect of a compromised cerebral circulation on cognitive function. We believe that cerebrovascular disease will be exacerbated in TGF+DB mice compared to TGF mice due to the effect of hyperglycemia on the microvasculature. In TGF+DB mice, we will also test whether age or gender contribute to the increased vulnerability of cognitive failure and cerebrovascular deficits. Finally, we will seek new targets for therapies that could be translated to patients in the future. The proposed study is relevant because multifactorial alterations are common in the elderly. We suggest that this model will help elucidate whether cerebrovascular disease and DB interplay in cognitive deficits or just coexist.
Dr. Hamel’s laboratory already has experience in combining cerebrovascular pathology and hypercholesterolemia in the same TGF mouse model. The proposed project is part of a larger initiative aimed at understanding the role of a compromised cerebral circulation in the appearance or manifestation of cognitive failure when combined to risk factors such as hypercholesterolemia, hypertension, and DB. The project fits with the priority research areas 3 and 4.