Alzheimer's disease (AD) is a major rising global health threat in the 21st century associated with dementia and decline in cognition and memory. Significant morbidity and mortality is associated with AD. Effective preventive therapies and and treatments of AD are lacking and there is still poor understanding of how genetic variations, environment and lifestyle provide a risk to AD. This project seeks to close this knowledge gap by examining the ability of let-7 microRNA family to control neuropathologic and cognitive impairments in murine models of AD acting in part to influence microglial and peripheral immune cell activation and inflammatory gene expression impacting on amyloid plaque removal and neuronal survival. Decreased Let-7 expression has been detected AD patients and Let-7 controls the expression of multiple pro- inflammatory and anti-inflammatory genes implicated in AD disease including IL6 and IL10. To perform our studies, we will reduce let-7 activity in vivo, by manipulating let-7 activity using genetically modified mice with null mutations in let-7bc-cluster (comprised of let-7b and let-7c2 loci) and let-7afd-cluster (comprised of let-7a1, let-7d, let-7f1 loci) respectively introduced into the 5xFAD mice which manifests aspects of AD. By altering let-7bc or let-7afd expression, different downstream targets of let-7 will be induced, thereby enhancing or blocking microglial and altering TH17/iTreg balance. The following specific Aims will be pursued: 1) Testing the hypothesis that absence of let-7afd-cluster will suppress the development of AD associated neuropathology and cognitive phenotypes seen in the 5xFAD mouse. 2) Test the hypothesis that the let-7bc-cluster exacerbates 5xFAD mice disease progression. Overall these Aims will be addressed through a combination of behavioral, cellular, immunological and neurohistopathological techniques. Findings derived will identify the role of let-7 and downstream targets in AD. Resulting studies may also lead to the development of effective new therapies in AD.
The overall goal of this proposal is to understand the function of let-7 microRNA family during Alzheimer's disease. Therapeutically, elucidating how let-7 functions may help us to develop new methods or tools for treatment of Alzheimer's disease and dementia.