Diabetes, Amyloid and Stroke

Grants and Contracts Details

Description

Metabolic disease is linked to obesity – especially mid-life obesity – a persistent problem in our society. An unexplained connection exists between type 2 diabetes mellitus (T2DM) and neurologic disorders, such as vascular dementia and Alzheimer’s disease (AD). The biological mechanism underlying this link is not known. As our population demographics shift towards an older average age, the potential confluence of obesity, diabetes and age related neurological dysfunction represents a potential public health disaster. The form of dementia afflicting individuals with a history of obesity and diabetes combines vascular pathology, strokes and AD related neuropathology, including deposits of the amyloid-â peptide (Aâ). It is not known if Aâ, either in the brain parenchyma or deposited within the cerebrovasculature, casues the vascular pathology or if some other aspect of diabetes and obesity is reponsible. To explore this problem, we generated a novel line of mutant mice that become rapidly obese and diabetic, and develop amyloid neuropathology with increasing age. This unique mouse model (db/AD) does not overexpress disease related proteins or use artificial promoter systems, making it an ideal system for the study of how aberant gene regulation in metabolic disease can influence brain pathology. These mice develop significant age-related cerebrovascular pathology, including aneurysms and strokes. We propose to use our unique db/AD model to test the hypothesis that amyloid, and the Aâ peptide, is the cause of vascular pathology and strokes. We will utilize a therapeutic approach (currently in late-stage human clinical trials) to block deposition of amyloid in the brain, and determine if this is sufficient to prevent strokes and other cerebrovascular pathology. Since this approach has been shown to have a good safety profile in human trials, the clinical implications for the outcome of this study are significant. The major strengths of this proposal are the use of a novel mouse model with unique features, and an innovative approach to determine if the Aâ peptide is the specific component of the disease state responsible for the development of cerebrovascular pathology. This project has the potential to significantly advance our understanding of the major underlying causes of vascular dementia, and has significant implications for the treatment and prevention of age-related cerebrovascular disease.
StatusFinished
Effective start/end date1/1/1312/31/15

Funding

  • American Heart Association: $150,000.00

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