MicroRNAs have emerged as key factors in development, neurogenesis and synaptic functions in the central nervous system. the reduction in dendritic spine density in the primary hippocampal neurons treated with oligomeric A1-42 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 A-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 expression1,2. In the central nervous system, microRNAs have been shown to regulate development, survival, function and plasticity3,4,5. MicroRNAs and their precursors exist in synaptic fractions along with components of the microRNA machinery6, 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 Alzheimers disease (AD)7,8. However, little is known regarding whether restoring or reversal of deregulated microRNAs is usually capable of counteracting deficits in cognitive or synaptic dysfunctions in AD. Since AD-mediated cognitive deficits have been postulated as synaptic by origin9,10, one area that has been extensively researched is the study of aberrant amyloid beta peptide1-42 (A1-42)-mediated modulation of synaptic transmission and plasticity11. The most extensively documented synaptic phenomenon in this regard is usually long-term potentiation (LTP), which is usually inhibited by overexpression of APP genes12 and A administration13. Previously, we reported that miR-188-5p is usually up-regulated by LTP induction14. The protein level of neuropilin-2 (Nrp-2), which was confirmed to Mocetinostat be a direct target of miR-188-5p by performing a luciferase activity assay in our previous study14, was decreased during LTP induction. It is of interest whether atypical miR-188-5p expression can be seen in AD and leads to aberrant long-term synaptic plasticity, an underlying cellular mechanism of learning and memory15. Nrp-2 has been previously reported to serve as a negative regulator of spine development and synaptic structure, together with its ligand, semaphorin-3F (Sema-3F)16. Nrps are 130- to 140-kDa single transmembrane spanning glycoproteins that function as receptors for class 3 semaphorins, polypeptides essential for axonal guidance17,18 and for members of the vascular endothelial growth factor (VEGF) family, angiogenic cytokines16,18,19,20. Nrp-1 serves as a receptor for Sema-3A, which induces the collapse of the neuronal growth cone21,22. In this study, we found that oligomeric A1-42 treatment diminished miR-188-5p expression in primary hippocampal neurons and that miR-188-5p rescued the A1-42-mediated synapse elimination and synaptic dysfunctions. Moreover, the impairments in cognitive function and synaptic transmission observed in 7-month-old 5XFAD transgenic mice, which harbor 3 familial AD mutations of APP 695, namely the Swedish, Florida, and London mutations and 2 presenilin1 (PSEN1) mutations (M146L and L286V), were ameliorated via viral-mediated expression of miR-188-5p. miR-188-5p expression was reduced and Nrp-2 was up-regulated in brain tissues from AD patients and 5XFAD mice. miR-188 gene has a cAMP response element (CRE) in its potential promoter region which would be shared with chloride channel 5 (mRNA expression was not significantly Rabbit Polyclonal to MRPL54. different from age-matched control subjects (Supplementary Fig. S1). Physique 1 miR-188-5p was significantly down-regulated in the brains from AD patients. Table 1 Information around the control subjects and Alzheimers disease patients. Oligomeric A1-42 reduced the expression of miR-188-5p A, which is the Mocetinostat main component of neuritic plaques in AD brains, is thought to be a causative factor in the Mocetinostat pathogenesis of the disease23. Among several aggregated forms of A observed in AD Mocetinostat brains, oligomeric A has been reported to play the most important role in disconnecting the synaptic network24,25. We examined the effects of oligomeric A1-42 on miR-188-5p expression and the protein level of Nrp-2, the molecular target of miR-188-5p in rat primary hippocampal neurons. Treatment with 5?M oligomeric A1-42 for 24?h significantly decreased miR-188-5p expression (0.52??0.13 vs. vehicle-treated group, p?=?0.03, n?=?11, Fig. 2a), but increased Nrp-2 protein in the neurons (1?M oligomeric A1-42 for 24?h, 1.30??0.36, gene in the rat genome via the UCSC genome browser, and found that gene is located at approximately 50?kb upstream from the transcriptional start site of the gene around the X-chromosome (Fig. 6a)..