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.
Highlights
Alzheimer's disease (AD), one of the major neurodegenerative disorders characterized by progressive memory loss and cognitive impairment, is mainly caused by the accumulation of amyloid β peptide (Aβ) and neurofibrillary tangles (Chen et al, 2017; Hardy & Selkoe, 2002)
Since the impaired synaptic plasticity was associated with the upregulation of miR‐134‐5p expression in rat hippocampal slices, we investigated if inhibition of miR‐134‐5p expression using miR‐134i could rescue late long‐term potentiation (LTP) in Aβ (1–42)‐treated hippocampal slices
The qRT‐PCR analysis showed that cAMP response element‐binding protein (CREB)‐1 and brain‐derived neurotrophic factor (BDNF) messenger RNAs (mRNAs) expression levels were significantly decreased in Aβ (1–42)‐treated hippocampal slices when compared to wild‐type control slices (Figure 4a, student's t test, p = .03 and 4C, student's t test, p = .006)
Summary
Exogenous application of Aβ (1–42) impairs long‐term potentiation (LTP), a cellular correlate of memory and synaptic tagging/capture (STC), a model to study associative plasticity in the hippocampus (Jiang et al, 2015; Krishna, Behnisch, & Sajikumar, 2016; Lei et al, 2016; Ma et al, 2014; Sharma et al, 2017). MiR‐134 was shown to mediate LTP and synaptic plasticity through the Sirtuin1‐CREB‐BDNF pathway in the hippocampus (Gao et al, 2010) Since it is not clear if the upregulation of miR‐134 expression in AD patients (Moradifard et al, 2018) causes plasticity deficit, in the present study, we have investigated the functional role of miR‐134‐5p in regulating long‐term plasticity and cellular associativity in Aβ (1–42)‐treated hippocampal CA1 pyramidal neurons
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