Mounting evidence suggests that epigenetic changes, including microRNA (miRNA) dysregulation, contribute to aging, psychiatric disorders and neurodegenerative disorders. Although modulations of miRNA function have generated promising clinical data for several diseases, miRNA?s roles in brain aging and Alzheimer?s disease (AD) have not been investigated thoroughly. During AD pathogenesis, dysregulation of insulin signaling is evident. Abnormal accumulation of Tau and amyloid beta is hypothesized to initiate a pathogenic cascade leading to AD. Given the critical role of these protein aggregations in AD, strategies to modulate tau and amyloid beta are actively being pursued as therapies. Toward that end, we seek to define the role of microRNAs (miRNAs), specifically miR-17-92, in AD pathogenesis. Instead of setting up a hypothesis based on the previously well-known proteins and concepts, we performed unbiased transcriptomics profiling experiments and identified miR-17-92 as the most strongly dysregulated miRNAs during brain aging. Remarkably, our finding is consistent with a recent landmark study by the NIH Common Fund?s Genotype-Tissue Expression (GTEx) consortium?s data using 11 human brain subregions. We hypothesize that such dysregulation of miR- 17-92 expression may directly contribute to aging process. Therefore, it will be critical to understand the functional effect of miR-17-92 decline on brain aging and try to restore its levels to ameliorate aging effect and AD pathogenesis. Mounting studies recently suggests that miRNA dysregulation may contribute to several neurodegenerative disorders, including AD. Interestingly, we found that miR-17-92 regulates tau phosphorylation and APP expression level possibly by modulating insulin signaling pathway. In this application, we propose to investigate the role of miR-17-92 in cognition and Alzheimer?s disease. We will determine how miR-17-92 affects learning and memory and AD-related neuropathology using novel AAV Tau mouse model and APP knock-in mouse model. Furthermore using several innovative in vivo methods, we will investigate the mechanism underlying the role of miR-17-92 in Tau and Abeta metabolism.

Public Health Relevance

Alzheimer's disease is clinically characterized by progressive memory loss and pathologically characterized by the accumulation of toxic protein, such as amyloid beta and Tau. In this project, we propose to study roles of a newly discovered biomolecule, microRNA, in cognition and toxic protein aggregation. Our study will offer novel mechanistic insights into Alzheimer's disease pathogenesis and brain aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG054102-03
Application #
9512654
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Opanashuk, Lisa A
Project Start
2016-09-01
Project End
2021-05-31
Budget Start
2018-06-15
Budget End
2019-05-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224