Project summary: The purpose of our study is to determine the role of synaptosomal microRNAs (miRNAs) in Alzheimer’s disease (AD) progression and pathogenesis. Synapses are the most important compartments of neuron that deliver signals to adjacent neuron and maintain healthy synaptic functions of the brain. Recently, several studies identified the miRNAs enrichments at synapse, synaptic vesicles and synaptosomes. However, the role of synapse-associated miRNAs in AD progression is completely unexplored. In the first part of our study, we identified synaptosome-specific miRNAs those were deregulated in AD and involved in nervous system development, cell junction organization, synapse assembly formation, and function of GABAergic synapse. The high expression of synaptosomal miRNAs were significantly correlated with Braak stage-based disease progression. Currently we are studying the protective and/or deleterious properties of synaptosomal miRNAs against Aβ and p-tau toxicities. The effects of synaptosomal miRNAs will be determined on overall synapse functions and synaptic activity. In second part we will determine the role of synaptosomal miRNAs in Aβ induced synaptic and cognitive dysfunction in AD. The impact of synaptosomal miRNAs will be studied on healthy neurons and AD neurons with Aβ induced toxicities. We will focus on neuronal processing, neuronal growth and network development and synaptic plasticity using APP primary neuronal cultures. Alteration of synaptosomal miRNAs expression and synaptic proteins will be studied with disease progression in APP transgenic (TG) and APP knockout (KO) mice. We will execute the synaptosome-specific miRNAs expression with various cognitive behavioral and biochemical tests in 2-, 6-, 12- and 18-month-old APP TG and APP KO mice lines relative to age-matched TG negative wild-type (WT) mice. Lastly, we will study the role of synaptosomal miRNAs in phosphorylated-tau (p-tau) induced synaptic and cognitive dysfunction in AD. The impact of synaptosomal miRNAs will be studied on p-tau induced toxicity in neurons, healthy neurons processing, neuronal growth and network development and synaptic plasticity using tau primary neuronal culture. Alteration of synaptosomal miRNAs and synaptic proteins will be studied with disease progression in Tau TG and Tau KO mice. We will execute the synaptosome-specific miRNAs expression with various cognitive behavioral and biochemical tests in 2-, 6-, 12- and 18-month-old tau TG and KO mice relative to WT mice. Our study outcome will provide the answers for - 1) deregulation of synaptosomal miRNAs at AD synapse, 2) synaptosome-associated miRNAs linked with Aβ and p-tau pathologies in AD, 3) Overall synapse function, synaptic activity, assessment of therapeutic value of synaptosome-associated miRNAs in AD.