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-ß (Aß) production and reduced clearance of Aß 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 the 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 the 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 AD mice, when miR-455-3p is overexpressed and what mechanisms occur in AD mice when
miR-455-3p is reduced. The proposed research will investigate the following 2 aims: 1) to determine the
protective effects of miR-455-3p against Aß and mitochondrial toxicities and synaptic/cognitive dysfunction at
different stages of AD progression, and 2) to determine the effects of depleted miR-455-3p on Aß 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.