Significance: Alzheimer’s disease (AD) is the most common form of age-related dementia, affecting over 5.8 million Americans. Diabetes affects 34 million Americans (90-95% of which is type 2 diabetes, T2D), of which 1.5 million were newly diagnosed in the previous year. Most of these “new” cases were 45-64 years old, also important to pre-AD etiology. About 88 million have pre-diabetes. Since comorbidity is common in humans, an integrated study of AD and diabetes would have significant translational impact. Our goal to unveil specific shared AD/T2D regulatory pathways is significant to lay groundwork for “co-treatment” of comorbid conditions Rationale: Understanding co-regulation of the T2D-AD axis will be beneficial for two widespread interlinked chronic disorders. AD neuropathology primarily consists of neuritic plaques of amyloid-β (Aβ) peptide, neuro- fibrillary tangles of hyperphosphorylated tau (τ), neuroinflammation, and synaptic loss. Hyperglycemia increases Aβ production. Other pathways that operate “through” T2D and “into” AD include brain insulin resistance, and diabetes-triggered elevation of inflammation and oxidative stress, exacerbating Aβ and tau aggregation. Such shared dyshomeostasis suggests shared dysregulation. One such dysregulatory avenue would be microRNAs (miRNA), small non-coding RNAs that modulate translation of proteins from mRNA. Hypothesis: Two specific miRNA species that are dysregulated in T2D (miR146a, miR200b) are also dysregulated in AD, and significant AD-associated immediate and downstream effects accompany this co- dysregulation. Approach: Combining non-genetic T2D animal models, pertinent (human neuronal and human neurovascular) culture manipulation, and human AD samples (and control brains). Aim 1: Test the hypothesis that T2D disruption of CNS protein levels is rescued by vascular expression of miR200b/miR146a. We will test disruption of protein levels in mouse brains and rescue by miR146a and 200b. Aim 2: Test the hypothesis that selected miRNAs directly interact with 3’-UTRs of AD-associated mRNAs. We will characterize miR146a and 200b effects on AD-related proteins and show that activities of miR200b and 146a in mouse models have counterparts in human-origin cells when treated with human miR200b and/or 146a. Aim 3: Test the hypothesis that T2D and AD similarly disrupt selected miRNAs in human brains. We will determine the extent to which miR200b and -146 are perturbed in T2D, AD, and T2D+AD autopsy brain samples. Impact & Future Plan: We will discover and manipulate a network of shared miRNA dysregulation in all stages of T2D/AD, allow regulatory progression of early disease stages to be known in parallel. We will study neuro- pathology in miRNA overexpression/AD cross transgenic models and induced T2D in AD Tg models. We will design experiments to track shared biochemical progression of T2D and AD, as well as T2D that does not progress into AD. The overall impact is to develop intentional regulat...