Abstract
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 Aβ1-42 treatment diminished miR-188-5p expression in primary hippocampal neuron cultures and that miR-188-5p rescued the Aβ1-42-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 Aβ1-42 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.
Highlights
MicroRNAs and their precursors exist in synaptic fractions along with components of the microRNA machinery[6], where they are poised to regulate neurotransmission
The impairments in cognitive function and synaptic transmission observed in 7-month-old 5XFAD transgenic mice, which harbor 3 familial Alzheimer’s disease (AD) mutations of APP 695, namely the Swedish, Florida, and London mutations and 2 presenilin[1] (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 (Clcn 5)
We examined the effects of oligomeric Aβ1-42 on miR-188-5p expression and the protein level of Nrp-2, the molecular target of miR-188-5p in rat primary hippocampal neurons
Summary
MicroRNAs and their precursors exist in synaptic fractions along with components of the microRNA machinery[6], where they are poised to regulate neurotransmission. The protein level of neuropilin-2 (Nrp-2), which was confirmed to be a direct target of miR-188-5p by performing a luciferase activity assay in our previous study[14], 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 memory[15]. Our results indicate that the reduction in miR-188-5p, which is expressed in a synaptic activity-dependent manner, in the brains of AD patients may contribute to the defective synapse elimination and cognition observed in the disease
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