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 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 .

The Regulation of microRNAs in Alzheimer's Disease

“…The recovery of cognitive function can be achieved by restoring the reduced microRNAs acting at the synaptic level. The abnormal down-regulation of miR-188-5p is reported in the cerebral cortices and hippocampus of AD patients when compared with age-matched control subjects (42). Dendritic spine and synapse loss are welldocumented in AD.…”

“…Long-term potentiation (LTP) is believed to be a synaptic mechanism underlying the storage of long-term memory in the brain. The replenishment of miR-188-5p can improve behavioral outcomes and enhance synaptic activity, importantly, and restore cognitive function in AD mouse models such as 5XFAD mice (42,43). However, some microRNAs are abnormally elevated in AD models and could have negative effects on neurons.…”

Down‐regulated expression of microRNA‐338‐5p contributes to neuropathology in Alzheimer's disease

“…However, it is still not clear whether undefined miRs that target BACE1 contribute to the development of AD neuropathology. In particular, only a few studies have been conducted to determine whether a reversal of miR(s) targeting BACE1 alleviates AD neuropathology in vivo (23,25,26). Our previous study demonstrated that overexpression of miR-188-3p, which also targets BACE1, ameliorates neuropathology and improves synaptic function in 5XFAD TG mice (25).…”

“…Previous studies have identified several miRs that target BACE1, a key enzyme responsible for Ab formation (20)(21)(22)(23)(24), but only a few studies have been conducted to determine whether restoration or reversal of dysregulated miRs targeting BACE1 is capable of reducing Ab production, which in turn, alleviates neuropathology of AD (23,25,26). In our previous miR microarray screening, we identified several deregulated miRs in the hippocampus of 5XFAD transgenic (TG) mice, a mouse model of AD (25).…”

Circulating MicroRNA-19b Identified From Osteoporotic Vertebral Compression Fracture Patients Increases Bone Formation

“…Plenty of studies have pointed to the involvement of miRNAs in various diseases, including cancer, (3)(4)(5)(6) heart diseases, (7,8) lung diseases, (9,10) nervous system disorders, (11,12) and even genetic diseases. (13)(14)(15) MicroRNAs can be transported in the extracellular circulation in several ways, including: (1) complexed with highdensity lipoproteins (HDL) or the Ago2 protein; (16) (2) encapsulated within microvesicles; (17) (3) accumulated in apoptotic bodies; (18) and (4) packaged within exosomes.…”