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Replenishment of microRNA-188-5p restores the synaptic and cognitive deficits in 5XFAD Mouse Model of Alzheimer's Disease.

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 A?1-42 treatment diminished miR-188-5p expression in primary hippocampal neuron cultures and that miR-188-5p rescued the A?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 A?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 A?-mediated pathophysiology in the disease.

SUBMITTER: Lee K

PROVIDER: S-EPMC5052619 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Replenishment of microRNA-188-5p restores the synaptic and cognitive deficits in 5XFAD Mouse Model of Alzheimer's Disease.

Lee Kihwan K Kim Hyunju H An Kyongman K Kwon Oh-Bin OB Park Sungjun S Cha Jin Hee JH Kim Myoung-Hwan MH Lee Yoontae Y Kim Joung-Hun JH Cho Kwangwook K Kim Hye-Sun HS

Scientific reports 20161006

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<sub>1-42</sub> treatment diminished miR-188-5p expression in primary hippocampal neuron cultures and that miR-188-5p rescued the Aβ<sub>1-42</sub>-mediated synapse elimination and synaptic dysfunctions. Moreover, the i ...[more]

PMID: 27708404

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Project description:BackgroundRibosomal protein S6 kinase 1 (S6K1) is a serine-threonine kinase that has two main isoforms: p70S6K (70-kDa isoform) and p85S6K (85-kDa isoform). p70S6K, with its upstream mammalian target of rapamycin (mTOR), has been shown to be involved in learning and memory and participate in the pathophysiology of Alzheimer's disease (AD). However, the function of p85S6K has long been neglected due to its high similarity to p70S6k. The role of p85S6K in learning and memory is still largely unknown.MethodsWe fractionated the postsynaptic densities to illustrate the differential distribution of p85S6K and p70S6K. Coimmunoprecipitation was performed to unveil interactions between p85S6K and the GluA1 subunit of AMPA receptor. The roles of p85S6K in synaptic targeting of GluA1 and learning and memory were evaluated by specific knockdown or overexpression of p85S6K followed by a broad range of methodologies including immunofluorescence, Western blot, in situ proximity ligation assay, morphological staining and behavioral examination. Further, the expression level of p85S6K was measured in brains from AD patients and AD model mice.Resultsp85S6K, but not p70S6K, was enriched in the postsynaptic densities. Moreover, knockdown of p85S6K resulted in defective spatial and recognition memory. In addition, p85S6K could interact with the GluA1 subunit of AMPA receptor through synapse-associated protein 97 and A-kinase anchoring protein 79/150. Mechanistic studies demonstrated that p85S6K could directly phosphorylate GluA1 at Ser845 and increase the amount of GluA1 in synapses, thus sustaining synaptic function and spine densities. Moreover, p85S6K was found to be specifically decreased in the synaptosomal compartment in the brains of AD patients and AD mice. Overexpression of p85S6K ameliorated the synaptic deficits and cognitive impairment in transgenic AD model mice.ConclusionsThese results strongly imply a significant role for p85S6K in maintaining synaptic and cognitive function by interacting with GluA1. The findings provide an insight into the rational targeting of p85S6K as a therapeutic potential for AD.

Dataset Information

Replenishment of microRNA-188-5p restores the synaptic and cognitive deficits in 5XFAD Mouse Model of Alzheimer's Disease.

Publications

Replenishment of microRNA-188-5p restores the synaptic and cognitive deficits in 5XFAD Mouse Model of Alzheimer's Disease.

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