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

Abstract

Alzheimer's disease (AD) is a leading cause of dementia. However, the mechanisms responsible for development of AD, especially for the sporadic variant, are still not clear. In our previous study, we discovered that a small noncoding RNA (miR‐188‐3p) targeting β‐site amyloid precursor protein cleaving enzyme (BACE)‐l, a key enzyme responsible for Aβ formation, plays an important role in the development of neuropathology in AD. In the present study, we identified that miR‐338‐5p, a new miRNA that also targets BACE1, contributes to AD neuropathology. We observed that expression of miR‐338‐5p was significantly down‐regulated in the hippocampus of patients with AD and 5XFAD transgenic (TG) mice, an animal model of AD. Overexpression of miR‐338‐5p in the hippocampus of TG mice reduced BACE1 expression, Aβ formation, and neuroinflammation. Overexpression of miR‐338‐5p functionally prevented impairments in long‐term synaptic plasticity, learning ability, and memory retention in TG mice. In addition, we provide evidence that down‐regulated expression of miR‐338‐5p in AD is regulated through the NF‐κB signaling pathway. Our results suggest that down‐regulated expression of miR‐338‐5p plays an important role in the development of AD.—Qian, Q., Zhang, J., He, F.‐P., Bao, W.‐X., Zheng, T.‐T., Zhou, D.‐M., Pan, H.‐Y., Zhang, H., Zhang, X.‐Q., He, X., Sun, B.‐G., Luo, B.‐Y., Chen, C., Peng, G.‐P. Down‐regulated expression of microRNA‐338‐5p contributes to neuropathology in Alzheimer's disease. FASEB J. 33,4404–4417 (2019). http://www.fasebj.org

Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases

“…Downregulated miR-29a/29b1/c, miR-338-5p and miR-16 are all linked to increased Aβ-mediated neurotoxicity in vitro and in vivo [113]. Among those microRNAs, miR-338-5p also regulates NF-kB signaling and promotes neuroinflammation [122]. In vivo studies with mouse models also showed that miR-34a promotes Aβ accumulation and cognition by promoting BACE-1 expression and β-secretase activity.…”

“…miR-16 can reduce BACE1 expression and attenuate Aβ-mediated neurotoxicity. miR-338-5p also regulates BACE-1 expression by targeting its mRNA, and expression of this micro-RNA leads to increased Aβ formation in brain tissues [122]. Downregulated miR-29a/29b1/c, miR-338-5p and miR-16 are all linked to increased Aβ-mediated neurotoxicity in vitro and in vivo [113].…”

Extracellular Vesicles Loaded miRNAs as Potential Modulators Shared Between Glioblastoma, and Parkinson’s and Alzheimer’s Diseases

“…This is an important finding that would corroborate the theory of vascular dysfunction and hypoperfusion during the pathogenesis of AD ( Govindpani et al, 2019 ). Similarly, overexpressed miRNA-338 targets BACE1 and reverts neuroinflammation and Aβ-amyloid formation ( Qian et al, 2019 ). Interestingly, the knockdown of this miRNA by the injection of the miRNA-338-sponge in mice brain promoted spontaneous neoplasm formation, histologically reminiscent of GBM with neuronal morphological disorganization and increased proliferation ( Howe et al, 2017 ).…”

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

“…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 ]. Similarly, overexpression of miR-338-5p and miR-181 functionally prevented impairments in synaptic plasticity, learning ability, and memory retention in an animal model of AD [ 85 , 86 ]. Furthermore, overexpression of miR-153 has provided new insight into the molecular mechanism of presynaptic plasticity impairment at the miRNA level and suggests that chronic brain hypoperfusion obstructs presynaptic vesicle fusion with the presynaptic membrane via miR-153-mediated downregulation of multiple synaptic vesicle-related proteins [ 87 ].…”