MicroRNA‐134‐5p inhibition rescues long‐term plasticity and synaptic tagging/capture in an Aβ(1–42)‐induced model of Alzheimer’s disease

Abstract

Progressive memory loss is one of the most common characteristics of Alzheimer's disease (AD), which has been shown to be caused by several factors including accumulation of amyloid β peptide (Aβ) plaques and neurofibrillary tangles. Synaptic plasticity and associative plasticity, the cellular basis of memory, are impaired in AD.Recent studies suggest a functional relevance of microRNAs (miRNAs) in regulating plasticity changes in AD, as their differential expressions were reported in many AD brain regions. However, the specific role of these miRNAs in AD has not been elucidated. We have reported earlier that late long-term potentiation (late LTP) and its associative mechanisms such as synaptic tagging and capture (STC) were impaired in Aβ (1-42)-induced AD condition. This study demonstrates that expression of miR-134-5p, a brain-specific miRNA is upregulated in Aβ (1-42)-treated AD hippocampus.Interestingly, the loss of function of miR-134-5p restored late LTP and STC in AD.In AD brains, inhibition of miR-134-5p elevated the expression of plasticity-related proteins (PRPs), cAMP-response-element binding protein (CREB-1) and brain-derived neurotrophic factor (BDNF), which are otherwise downregulated in AD condition.The results provide the first evidence that the miR-134-mediated post-transcriptional regulation of CREB-1 and BDNF is an important molecular mechanism underlying the plasticity deficit in AD; thus demonstrating the critical role of miR-134-5p as a potential therapeutic target for restoring plasticity in AD condition.

Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer

“…BDNF is able to relieve the inhibition of LIM kinase 1 translation, and in this manner contribute to synaptic development, maturation and/or plasticity [ 56 ]. Recently, Baby et al [ 57 ] found that miR-134 mediates post-transcriptional regulation of CREB1 and BDNF, as previously described by Gao et al [ 58 ], who demonstrated that mutant mice lacking Sirtuin 1 (SIRT1) catalytic activity shows reduction in both CREB and BDNF proteins and upregulation of miR-134. Thus, higher levels of miR-134 negatively regulate synaptic plasticity [ 58 ].…”

Plasma microRNAs biomarkers in mild cognitive impairment among patients with type 2 diabetes mellitus

“…Gao and co-workers [ 39 ] reported that miR-134 mediates late long term potentiation (LTP) and synaptic plasticity through the Sirtuin1- cAMP-response-element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) pathway in the hippocampus. miR‐134 post‐transcriptionally regulates the expression of CREB and BDNF in AD cases [ 40 ]. CREB and BDNF are two important plasticity-related proteins that are involved in synaptic plasticity and memory formation [ 41 ].…”

Applications of Acupuncture Therapy in Modulating the Plasticity of Neurodegenerative Disease and Depression: Do MicroRNA and Neurotrophin BDNF Shed Light on the Underlying Mechanism?

“…There is now considerable evidence that the dysregulation of miRNAs correlates with the progression and severity of AD [ 78 ]. The differential expression of miRNAs has been reported in many brain regions [ 79 ]. miRNAs can also regulate synaptic transmission and plasticity in the hippocampus and neocortex and regulate memory formation [ 80 ].…”

“…Research has further confirmed that genetic deletion of miR-132 in mice promotes A β deposition, leading to impaired memory and enhanced Tau pathology [ 81 ]. However, the upregulation of miR-142-5p and miR-134-5p expression contributes to the pathogenesis of AD by triggering synaptic dysfunction associated with A β -mediated pathophysiology [ 79 , 82 ]. In learning memory aspects, miR-124 and miR-181a, which are two miRNAs that are upregulated in the hippocampus, are directly associated with deficits in synaptic plasticity [ 83 , 84 ].…”

“…A later study pointed out that both AD patients and AD models have high levels of miR-206 in the brain, which contributes to memory impairments by suppressing the expression of BDNF [ 95 , 96 ]. Similarly, recent evidence suggests that the miR-134-5p-mediated posttranscriptional regulation of CREB-1 and BDNF is an important molecular mechanism underlying plasticity deficits in AD [ 79 ]. Luciferase assays confirmed that miR-30a-5p, miR-195, and miR-613 can target specific sequences surrounding the proximal polyadenylation site within the BDNF 3′-untranslated region [ 61 , 97 ].…”