MicroRNAs have emerged as key factors in development, neurogenesis and synaptic functions in the central nervous system. In the present study, we investigated a pathophysiological significance of microRNA-188-5p (miR-188-5p) in Alzheimer's disease (AD). We found that oligomeric Aβ 1-42 treatment diminished miR-188-5p expression in primary hippocampal neuron cultures and that miR-188-5p rescued the Aβ 1-42 -mediated synapse elimination and synaptic dysfunctions. Moreover, the impairments in cognitive function and synaptic transmission observed in 7-month-old five familial AD (5XFAD) transgenic mice, were ameliorated via viral-mediated expression of miR-188-5p. miR-188-5p expression was down-regulated in the brain tissues from AD patients and 5XFAD mice. The addition of miR-188-5p rescued the reduction in dendritic spine density in the primary hippocampal neurons treated with oligomeric Aβ 1-42 and cultured from 5XFAD mice. The reduction in the frequency of mEPSCs was also restored by addition of miR-188-5p. The impairments in basal fEPSPs and cognition observed in 7-month-old 5XFAD mice were ameliorated via the viral-mediated expression of miR-188-5p in the hippocampus. Furthermore, we found that miR-188 expression is CREB-dependent. Taken together, our results suggest that dysregulation of miR-188-5p expression contributes to the pathogenesis of AD by inducing synaptic dysfunction and cognitive deficits associated with Aβ-mediated pathophysiology in the disease.MicroRNAs are non-coding RNA molecules with a length of approximately 22 nucleotides, which serve as post-transcriptional regulators of gene expression 1,2 . In the central nervous system, microRNAs have been shown to regulate development, survival, function and plasticity [3][4][5] .MicroRNAs and their precursors exist in synaptic fractions along with components of the microRNA machinery 6 , where they are poised to regulate neurotransmission. Furthermore, dysfunction of microRNAs within neurons and alterations in microRNA expression have been associated with the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) 7,8 . However, little is known regarding whether restoring or reversal of deregulated microRNAs is capable of counteracting deficits in cognitive or synaptic dysfunctions in AD.Since AD-mediated cognitive deficits have been postulated as synaptic by origin 9,10 , one area that has been extensively researched is the study of aberrant amyloid beta peptide 1-42 (Aβ 1-42 )-mediated modulation of synaptic transmission and plasticity 11 . The most extensively documented synaptic phenomenon in this regard is long-term potentiation (LTP), which is inhibited by overexpression of APP genes 12 and Aβ administration 13 .

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