Project Summary The purpose of the proposed research is to better understand the impact of microRNA-455-3p (miR- 455-3p) in Alzheimer’s disease (AD). AD is a progressive neurological disorder, characterized by an increase in amyloid-β (Aβ) production and reduced clearance of Aβ from AD-affected brain regions, leading to synaptic damage, hyperphosphorylated tau, mitochondrial structural and functional changes, inflammatory responses, deregulation of microRNAs (miRNAs), and neuronal loss. MicroRNAs regulate the cellular events at genomic and proteomic levels through the modulation of targeted genes. MicroRNAs also participate in inter-and- intracellular communication and the transportation from brain to extracellular fluids. In an AD state, endogenous levels of miRNAs change in AD affected tissues, and the miRNAs are released into the peripheral system. A preliminary study analyzing global miRNA in the serum of non-demented healthy persons, subjects with mild cognitive impairment and AD patients found miR-455-3p increasingly upregulated as disease progressed. This upregulation was verified in postmortem brains from additional persons with AD, AD cerebrospinal fluid, AD fibroblasts, and AD B-lymphocytes, and in the brains from APP transgenic mice. Subsequent preliminary studies revealed that miR-455-3p was a target to the 3’UTR of the APP gene and that an increase in miR-455-3p levels enhanced mitochondrial biogenesis proteins and the synaptic proteins. In the APP mice, miR-455-3p also was found to maintain healthy mitochondrial dynamics by decreasing the fission proteins and by increasing the fusion proteins. In contrast, when the production of endogenous miR-455-3p was inhibited, mutant APP and Abeta levels were increased. However, it is unclear, molecular mechanisms of neuroprotection in cells when miR-455-3p is overexpressed and what mechanisms occur in cells when miR- 455-3p is reduced. The proposed research will investigate the following 3 aims: 1) to determine the status of miR-455-3p levels during aging and progression of AD, 2) to determine the protective effects of miR-455-3p against Aβ and mitochondrial toxicities and cognitive dysfunction at different stages of AD progression, and 3) to determine the effects of depleted miR-455-3p on Aβ and mitochondrial toxicities and cognitive function at different stages of AD progression. The proposed studies will provide new insights into molecular mechanisms of miR-455-3p impacts beneficially and deleteriously.