miR-135a-5p mediates memory and synaptic impairments via the Rock2/Adducin1 signaling pathway in a mouse model of Alzheimer’s disease

Abstract

Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of Alzheimer’s disease (AD), but most abnormally expressed miRNAs found in AD are not regulated by synaptic activity. Here we report that dysfunction of miR-135a-5p/Rock2/Add1 results in memory/synaptic disorder in a mouse model of AD. miR-135a-5p levels are significantly reduced in excitatory hippocampal neurons of AD model mice. This decrease is tau dependent and mediated by Foxd3. Inhibition of miR-135a-5p leads to synaptic disorder and memory impairments. Furthermore, excess Rock2 levels caused by loss of miR-135a-5p plays an important role in the synaptic disorder of AD via phosphorylation of Ser726 on adducin 1 (Add1). Blocking the phosphorylation of Ser726 on Add1 with a membrane-permeable peptide effectively rescues the memory impairments in AD mice. Taken together, these findings demonstrate that synaptic-related miR-135a-5p mediates synaptic/memory deficits in AD via the Rock2/Add1 signaling pathway, illuminating a potential therapeutic strategy for AD.

Improved cognitive impairments by silencing DMP1 via enhancing the proliferation of neural progenitor cell in Alzheimer‐like mice

“…The Morris water maze was constructed to evaluate the spatial memory of SAMP8 and SAMR1 mice(Zheng et al, 2021 ). Briefly, the swimming tank water temperature was maintained between 30°C and 37°C, edible melanin was poured into the water to make opaque.…”

The role of pathological tau in synaptic dysfunction in Alzheimer’s diseases

“…Enhancing KIBRA levels or restoring the downstream signal transmission at postsynapses may be another strategy for AD therapeutic intervention [ 96 ]. In addition, miR-135a-5p, which is reduced in excitatory hippocampal neurons in a tau-dependent manner in AD mice, mediates the cytoskeleton re-organization disorder and synaptic impairments in these excitatory hippocampal neurons [ 97 ]. miRNAs are the most important post-transcriptional regulators, acting as fine-tuners for synaptic plasticity, and how they interact with pathological tau to induce postsynaptic dysfunction needs to be further investigated.…”

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“…It phosphorylates various substrates, including Lin-11/Isl-1/Meg-3 (LIM) kinase (LIMK), Myosin light chain (MLC), and MLC phosphatase (MLCP). ROCK influences amyloid-beta production, NFT formation, and neuroinflammatory regulation, affecting AD incidence [ 50 , 51 , 52 , 53 ].…”