Grants and Contracts Details
Description
Diseases that mimic Alzheimer’s disease (AD) constitute a powerful and understudied cause of cognitive impairment in the elderly. Probably the most important of these “AD mimics” is HS-Aging. Hippocampal sclerosis (HS) can be associated with different underlying causes; HS-Aging refers to the neurodegenerative disease that afflicts older persons. We produced recently the first genome-wide association study (13) that found a polymorphism that is associated with HS-Aging pathology, in the ATP-binding cassette, subfamily C member 9 (ABCC9) gene. ABCC9 protein regulates potassium channels, termed “KATP” channels. Remarkably, ABCC9 is a druggable target—both agonists and antagonists are used in humans. We observed that exposure to a popular drug class, sulfonylureas (oral anti-diabetic drugs), that target ABCC9 protein, is associated with increased risk for HS-Aging pathology, controlling for other factors including diabetes itself. This has important implications relevant to public health. However, our prior study analyzed exclusively retrospective cross-sectional data with a number of potential biases and confounders and a more rigorously controlled experiment would be preferable. Overall Hypothesis: ABCC9 regulation provides a pharmacological target to intervene in the main features of HS-Aging, including TDP-43 pathology. A key step forward to help test any such hypothesis is to generate the first animal preclinical model of HS-Aging. We aim to fill that knowledge gap. Based on exciting preliminary data, we propose a research program to address this gap and to test new agents for preclinical testing of an HS-Aging therapeutic candidate drug, nicorandil.
Project Objectives/Specific Aims:
1. Develop the first preclinical model of HS-Aging: GRN-KO mice that have been reported on before. Our studies indicate age-related P-TDP-43 pathology in a distribution that resembles HS-Aging in humans.
2. Test in the mouse model the hypothesis that a sulfonylurea drug (glimepiride) which antagonizes ABCC9, exacerbates HS-Aging pathology and behavior.
3. Test in the mouse model the hypothesis that nicorandil, which opens the potassium channel (the opposite activity as sulfonylureas), improves pathology and behavior and thus constitutes a therapeutic strategy.
Status | Finished |
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Effective start/end date | 11/15/14 → 3/1/16 |
Funding
- Alzheimers Drug Discovery Foundation: $149,996.00
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