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Description

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, currently affecting more than five million people in the U.S.A. The vast majority of AD cases are sporadic, with no clear etiology. It is well-documented that lifestyle and overall health play a role in the development of the disease. A connection exists between risk for AD and Type 2 Diabetes Mellitus (T2DM), a metabolic disease that is linked to obesity. The mechanism that underlies this epidemiological connection is unknown. Recent neuropathology studies have shown that AD cases that have a history of T2DM and obesity have substantially more cerebrovascular pathology, but have either the same or lesser amounts of neuritic plaques and neurofibrillary tangles. It may be that changes in the cerebrovasculature alter the threshold for the development of AD, or that individuals with AD and a history of obesity represent cases of mixed AD and vascular dementia. This proposal considers the possibility that these elements are connected through defective leptin signaling, since individuals with a history of obesity and diabetes are leptin resistant. Leptin is an adipocyte-derived peptide hormone that regulates satiety and hunger via signaling through the leptin receptor (LepR), and these receptors are expressed throughout the brain. To explore the connection between leptin resistance, obesity and AD, we created a unique mouse line (db/AD) that combines features of these pathophysiologic states. These mice are resistant to leptin (the LepR is inactivated), become rapidly obese and diabetic, and develop AD-related neuropathology with increasing age. These mice also develop a striking phenotype of cerebrovascular pathology, including aneurysms, strokes and marked changes in vascular density. In order to directly test the hypothesis that leptin resistance is the underlying cause of these effects, we propose to selectively replace the defective LepR in the neocortex with a functional version via adeno-associated virus, thereby restoring leptin sensitivity. Preliminary tests indicate that we are able to target the replacement to the neocortex without affecting the hypothalamus, and the animals remain hyperphagic and retain their metabolic disease phenotype. We therefore believe that this approach will allow us to separate the effects of leptin on the development of neuropathology from the many complex problems associated with obesity and systemic metabolic disease. If leptin resistance is the cause of the substantial neuropathology in the db/AD mice, then restoring leptin sensitivity will slow or reverse the phenotype. Alternatively, if restoring leptin sensitivity fails to attentuate the development of neocortical pathology, then we will be able to rule out its involvement and conclude that some other aspect of metabolic disease is responsible. This project, utilizing a novel and innovative mouse model, has the potential to significantly advance our understanding of the association between obesity, diabetes, and dementia. If there is a clear connection between leptin, leptin resistance and neuropathology, patients may one day benefit from preventative of therapeutic strategies targeting leptin pathways.
StatusFinished
Effective start/end date9/1/145/31/16

Funding

  • National Institute on Aging: $407,606.00

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