Project Summary Alzheimer’s disease (AD) is one of the most common aging-related diseases, affecting more than 5.5 million Americans age 65 and older and thus creating enormous socioeconomic burden. To date there is no cure for AD, due to our limited understanding of AD and biological processes of aging. We have found that two homologous miRNAs, miR-204 and miR-211, are essential for aged joint cells to maintain healthy homeostasis to counteract osteoarthritis (OA) pathogenesis. Interestingly, the mouse model with double knockout (dKO) of miR-204 and miR-211 displayed multiple pathological changes, mostly aging-related, such as OA in joints, hypermature cataracts with rupture, uveal melanosis, and retinal dysplasia in eyes, follicular dysplasia in skins, and valvular endocardiosis in hearts. Particularly, accelerated aging appears to occur in the brain of the dKO mice. Thus, the dKO mice may represent a unique, comprehensive model of aging. Deep sequencing of miRNAs has demonstrated that miR-204 is dominantly expressed in brain, and bioinformatic analysis reveals that multiple AD-associated genes may be targeted by miR-204/-211. In consideration of multiplexed aging phenotypes in the dKO mice, we hypothesize that miR-204 and miR-211 play important roles in brain pathophysiology and miR-204/-211 loss-of-function may exacerbate the pathogenesis of AD. Thus, we propose two Specific Aims in this supplement to expand our study of miRNA role in OA on AD, both diseases involving dysregulation of biological processes of aging. In Aim 1, we will identify AD-associated genes targeted by miR-204/-211 in brain cells, and in Aim 2, we will determine if miR-204/-211 loss-of-function exacerbates AD pathogenesis in a mouse model of AD. New insights uncovered from this study will deepen our understanding of AD and shed light into how accelerated aging occurs, thus advancing the development of innovative therapeutic options to treat numerous aging-related disorders including AD and OA.