Down-regulated expression of microRNA-338-5p contributes to neuropathology in Alzheimer’s disease.
Open accessAbstract
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)-1, 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.
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MiR-338 can promote myelination in the nervous system, and over-expression of miR-338 can enhance oligodendrocyte differentiation while inhibiting myelin negative regulators Sox6 and Hes5, therefore promoting myelin formation.
“MiR-338 can promote myelination in the nervous system, and over-expression of miR-338 can enhance oligodendrocyte differentiation while inhibiting myelin negative regulators Sox6 and Hes5, therefore promoting myelin formation [36].”
miR-338-5p is a dual-pathway regulator affecting both neuron-derived amyloid production and glial-derived myelin synthesis.
“Downregulation of miR-338-5p increases BACE1 expression, potentially accelerating Aβ accumulation, while simultaneously blocking myelin gene induction, making miR-338-5p a rare dual-pathway regulator affecting both neuron-derived amyloid production and glial-derived myelin synthesis (Qian et al., 2018).”
From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Qian et al., 2018
miR-338-5p is an oligodendroglial miRNA that is reduced in AD brains.
“miR-338-5p is another oligodendroglial miRNA reduced in AD brains.”
From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Qian et al., 2018
Downregulation of miR-338-5p increases BACE1 expression, potentially accelerating Aβ accumulation, and blocks myelin gene induction.
“Downregulation of miR-338-5p increases BACE1 expression, potentially accelerating Aβ accumulation, while simultaneously blocking myelin gene induction, making miR-338-5p a rare dual-pathway regulator affecting both neuron-derived amyloid production and glial-derived myelin synthesis (Qian et al., 2018).”
From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Qian et al., 2018
miR-338-5p targets BACE1 and the oligodendrocyte transcription factor SOX6.
“It targets BACE1 and the oligodendrocyte transcription factor SOX6, which has been linked to amyloid burden to impaired OL maturation (Qian et al., 2018).”
From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Qian et al., 2018
Oligodendrocyte miRNAs, most prominently miR-219-5p and miR-338-5p, bridge myelin maintenance, OPC maturation, and tau-kinase or APP/BACE1 regulation, linking white-matter degeneration to classical AD pathology.
“Oligodendrocyte miRNAs, most prominently miR-219-5p and miR-338-5p, bridge myelin maintenance, OPC maturation, and tau-kinase or APP/BACE1 regulation, linking white-matter degeneration to classical AD pathology (Dugas et al., 2010; Li et al., 2018; Qian et al., 2018).”
From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Qian et al., 2018
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“repair after spinal cord injury [20] and decreased expression of miR-338-5p contributes to the development of AD [21].”
BackgroundLi, X., Zhao, J., Li, Z., Zhang, L., & Huo, Z. (2020) · Neural Plasticity · doi:10.1155/2020/8850653 · Cited by 35 · see citing works
MicroRNAs and Synaptic Plasticity: From Their Molecular Roles to Response to Therapy
Mohammadi, A. H., Seyedmoalemi, S., Moghanlou, M., Akhlagh, S. A., Talaei, S. A., Hamblin, M. R., Jafari, A., & Mirzaei, H. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02907-2 · Cited by 33 · see citing works
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“Similarly, overexpressed miRNA-338 targets BACE1 and reverts neuroinflammation and Aβ-amyloid formation (Qian et al., 2019).”
BackgroundAlhenaky, A., Alhazmi, S., Alamri, S. H., Alkhatabi, H. A., Alharthi, A., Alsaleem, M. A., Abdelnour, S. A., & Hassan, S. M. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13226960 · Cited by 24 · see citing works
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“…by NF-κB signaling, whereas hippocampal overexpression of miR-338-5p in 5xFAD mice may diminish AD pathology, for example by reducing BACE1 and Aβ expression, suppressing neuroinflammation, and restoring long-term synaptic plasticity, as well as learning capacity and memory (Qian et al., 2019).”
BackgroundMicroRNAs and synapse turnover in Alzheimer’s disease
Dalal, S., Ramirez-Gomez, J., Sharma, B., Devara, D., & Kumar, S. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102377 · Cited by 21 · see citing works
MicroRNAs in Learning and Memory and Their Impact on Alzheimer’s Disease
Wang, I., Ho, P., & Tsai, K. (2022) · Biomedicines · doi:10.3390/biomedicines10081856 · Cited by 21 · see citing works
“miR‐338‐5p is also associated with neuronal differentiation, neurogenesis, and neuronal protective effects through the negative regulation of BCL2L11, which attenuates amyloid plaque deposition, neuroin‐ flammation, and neuronal apoptosis [68,69].”
BackgroundInfluentialZhang, Q., Yang, P., Pang, X., Guo, W., Sun, Y., Wei, Y., & Pang, C.-Y. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.1069606 · Cited by 20 · see citing works
“It has been reported that negatively regulated miRNA-mRNA pairs contribute to the improvement of AD and provide new reliable targets for the treatment of AD (Fu et al., 2019; Qian et al., 2019; Chen et al., 2021).”
BackgroundTasker, R., Rowlands, J., Ahmed, Z., & Pietro, V. D. (2021) · Cells · doi:10.3390/cells10123479 · Cited by 18 · see citing works
Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?
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A review on gut microbiota and miRNA crosstalk: implications for Alzheimer’s disease
Ayyanar, M. P., & Vijayan, M. (2024) · GeroScience · doi:10.1007/s11357-024-01432-5 · Cited by 23 · see citing works
“In AD, miR-15b, miR-29c [159], miR-31 [160], miR-107 [161], miR-200a-3p [162], and miR-388-5p [163] are capable of directly targeting BACE1, thereby decreasing Aβ build up and serving a protection against AD.”
The Role of Non-Coding RNAs in Mitochondrial Dysfunction of Alzheimer’s Disease
Abed, S., Ebrahimi, A., Fattahi, F., Kouchakali, G., Khaniani, M. S., & Derakhshan, S. M. (2024) · Journal of Molecular Neuroscience · doi:10.1007/s12031-024-02262-y · Cited by 16 · see citing works
“An investigation into the regulation of mitochondrial function by miRNAs demonstrated that miR-338 overexpression decreased ATP generation, metabolic activity, and mitochondrial oxygen consumption (Qian et al. 2019).”
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Exosomes and non-coding RNAs: bridging the gap in Alzheimer’s pathogenesis and therapeutics
Chunhui, G., You, Y., Chen, J., Luo, N., & Li, F. (2025) · Metabolic Brain Disease · doi:10.1007/s11011-024-01520-7 · Cited by 13 · see citing works
“Highly expressed miR-29c-3p (Sha et al. 2021 ), and miR-338-5p (Qian et al. 2019), and lowly expressed miR-27a (Hu et al. 2021 ), miR-128 (Liu et al. 2019 ), and miR-140-5p (Khodabakhsh et al. 2023), act on downstream targets and pathways to exert inhibitory effects on inflammatory responses (Table…”
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Epigenetic Regulation of Amyloid-beta Metabolism in Alzheimer’s Disease
He, C., Huang, Z., Yu, C.-C., Wang, H., Zhou, H., & Kong, L.-H. (2020) · Current Medical Science · doi:10.1007/s11596-020-2283-0 · Cited by 11 · see citing works
Potential Alzheimer’s disease drug targets identified through microglial biology research
Lepiarz‐Raba, I., Hidayat, T., Hannan, A. J., & Jawaid, A. (2024) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2024.2335210 · Cited by 9 · see citing works
“For instance, miR-124 and miR-338 can reduce Aβ production by targeting BACE in neurons and also inhibit microglial inflammation [76,77].”
BackgroundSmall RNA Profiles of Brain Tissue-Derived Extracellular Vesicles in Alzheimer’s Disease
Huang, Y., Driedonks, T. A. P., Cheng, L., Turchinovich, A. A., Pletniková, O., Redding‐Ochoa, J., Troncoso, J. C., Hill, A. F., Mahairaki, V., Zheng, L., et al. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230872 · Cited by 10 · see citing works
“Other EV-associated miRNAs that were downregulated in our study have been shown to regulate A (cid:2) PP cleavage [50], modulate neuroinflammation [51], and control migration of cortical neurons [52, 53].”
Bouter, Y., Kacprowski, T., Rößler, F., Jensen, L. R., Kuss, A. W., & Bayer, T. A. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.580524 · Cited by 10 · see citing works
“Notably, the expression of miR-338-5p was significantly down-regulated in the hippocampus of patients with AD and 5XFAD transgenic mice (Qian et al., 2019).”
BackgroundZhu, D., Zhang, J., Gao, F., Hu, M., Hashem, J., & Chen, C. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114292 · Cited by 9 · see citing works
Schmidt, A. T., Hicks, S. D., Bergquist, B. K., Maloney, K. A., Dennis, V. E., & Bammel, A. C. (2024) · Genes · doi:10.3390/genes15111433 · Cited by 8 · see citing works
The Function of microRNAs in Pulmonary Embolism: Review and Research Outlook
Luo, M., Du, M., Shu, C., Liu, S., Li, J., Zhang, L., & Li, X. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.743945 · Cited by 7 · see citing works
Zeng, H.-X., Qin, S.-J., Andersson, J., Li, S.-P., Zeng, Q.-G., Li, J.-H., Wu, Q.-Z., Meng, W.-J., Oudin, A., Kanninen, K. M., et al. (2024) · Environmental Pollution · doi:10.1016/j.envpol.2024.125440 · Cited by 8 · see citing works
The Neuroepigenetic Landscape of Vertebrate and Invertebrate Models of Neurodegenerative Diseases
Sundaramoorthy, T. H., & Castanho, I. (2022) · Epigenetics Insights · doi:10.1177/25168657221135848 · Cited by 6 · see citing works
Li, J., Liu, L., Sun, S., Liu, C., & Yin, P. (2026) · Medicine · doi:10.1097/md.0000000000046851 · Cited by 5 · see citing works
“[36,37] miR-132 plays a multifaceted role in neuronal development, participating in axonal elongation, cell migration, and plasticity regulation; notably, it exhibits the most pronounced reduction among all miRNAs in the brains of AD patients.”
Rahnama, M., Abdul-Tehrani, H., Mohammadi, M. R., Mirzaie, M., Jahandideh, P., & Memari, A. H. (2024) · Journal of Neurorestoratology · doi:10.1016/j.jnrt.2024.100096 · Cited by 5 · see citing works
MicroRNA and Alzheimer’s disease: Diagnostic biomarkers and potential therapeutic targets
Huang, Y., Chen, Y., He, Z., Lu, W., Lai, H., Wang, Y., & Wang, J. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-25-00002 · Cited by 3 · see citing works
“…miR-125b-5p, miR-31, miR-338-5p, miR-186, and miR-200a-3p also specifically directly target BACE1 mRNA, leading to a reduction in its expression and activity with decreased production of Aβ (Kim et al., 2016b; Qian et al., 2019; Wang et al., 2019; Barros-Viegas et al., 2020; Li et al., 2020).”
Deciphering and manipulating the epigenome for the treatment of Parkinson’s and Alzheimer’s disease
Okechukwu, C. E. (2021) · MGM Journal of Medical Sciences · doi:10.4103/mgmj.mgmj_90_20 · Cited by 3 · see citing works
Azam, H. M. H., Mumtaz, M., Rödiger, S., Schierack, P., Hussain, N., & Ambreen, A. (2025) · Neurological Sciences · doi:10.1007/s10072-025-08419-w · Cited by 3 · see citing works
microRNAs Mediate Signaling Pathways in Alzheimer’s Disease: Biomarkers and Therapeutic Targets
Rezayof, A., Ghasemzadeh, Z., & Kouhkan, F. (2024) · Springer eBooks · doi:10.1007/978-3-030-80662-0_39 · Cited by 2 · see citing works
Yuan, X., Wei, Y., Ao, T., Gong, K., Sun, Q., Zheng, Z., Hagiwara, H., & Ao, Q. (2020) · Journal of Molecular Neuroscience · doi:10.1007/s12031-020-01689-3 · Cited by 2 · see citing works
“microRNA-338 to be critical for the function of the nervous system, where it promotesmyelination (Qian et al. 2019; Zhao et al. 2010).”
BackgroundAl‐Hawary, S. I. S., Ali, A. Y., Mustafa, Y. F., Margiana, R., Ilyasovna, S. M., Ramadan, M. F., Almalki, S. G., Alwave, M., Alkhayyat, S., & Alsalamy, A. (2023) · Biotechnology Progress · doi:10.1002/btpr.3383 · Cited by 1 · see citing works
CircNCOA4 knockdown attenuates OGD-induced neuron injury through miR-338-5p/PDE4B axis
Wang, D., Xiao, S., Li, X., & Qi, W. (2023) · Experimental Brain Research · doi:10.1007/s00221-023-06702-w · Cited by 1 · see citing works
“1 3 that forced expression of miR-338-5p alleviated Alzheimer’s disease by reducing Aβ formation and neuroinflammation (Qian et al. 2019).”
Nguyen, H. D., & Kim, M.-S. (2024) · Epigenetics and human health · doi:10.1007/978-3-031-64788-8_10 · Cited by 1 · see citing works
Epigenetics and regenerative medicine
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Wu, Z., Huang, X., Cai, M., Huang, P., & Guan, Z. (2021) · Research Square · doi:10.21203/rs.3.rs-958945/v1
Research progress of exercise-regulated neuroinflammation on improving Alzheimer's disease
Huimin, W. U., ZHENG, Y., Yunliang, W. A. N. G., Wenqing, S. H. E. N., & He, B. (2022) · Shengming de Huaxue · doi:10.3724/abbs.20220191
Prospective use of miRNAs as biomarkers in the diagnosis of Alzheimer’s disease
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miR-338-5p exerts neuroprotective effects in Parkinson’s disease via targeting LRP1
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“This miRNA deficiency leads to the transcriptional derepression of BACE1, as miR-338-5p directly targets the 3 ′ -untranslated region (3 ′ -UTR) of the BACE1 mRNA to inhibit its translation [29].”
InfluentialCell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease
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Plasma multi-miRNA models classify Alzheimer’s, Parkinson’s, and Lewy body dementia
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Alzheimer’s Disease and MicroRNAs: Challenges and Future Perspectives in Diagnosis and Treatment
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Epigenetics in Alzheimer’s disease: from molecular mechanisms to emerging novel biomarkers
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“LncRNAs are long RNA transcripts ( > 200 nucleotides in length) that lack protein-coding potential but exert important epigenetic regulatory functions at transcriptional and post-transcriptional levels (Zhang et al., 2019; Wu et al., 2024).”
- Authors
- 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.
- Affiliations
- Zhejiang Chinese Medical University (CN)
- Louisiana State University Health Sciences Center New Orleans (US)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University (CN)
- Corresponding author
- Chen, Chu
- Peng, Guo-Ping
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2018-12-21
- Volume
- 33
- Issue
- 3
- Pages
- 4404-4417
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC6404576
- OpenAlex
- W2906227813
- Cited by
- 70
- References
- 64
- Citations by year
- 2026: 9 · 2025: 3 · 2024: 14 · 2023: 9 · 2022: 11 · 2021: 11 · 2020: 12 · 2019: 1
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The FASEB Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81471284)
- National Institutes of Health (R01NS076815)
- National Institute of Neurological Disorders and Stroke (R01AG058621)
- National Basic Research Program of China (2016YFC1306402)
- Zhejiang Chinese Medical University (2018ZR04)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, BACE1, hippocampus, neuroinflammation, NF-κB signaling, synaptic plasticity, memory impairment, 5xFAD mice, microRNA downregulation
- MeSH terms
- Alzheimer Disease, Animals, Cells, Cultured, Disease Models, Animal, Hippocampus, Humans, Inflammation, Male, Memory Disorders, Mice, Transgenic, Neuronal Plasticity, Neurons, Peptide Fragments, Recombinant Proteins, Down-Regulation, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, NF-kappa B, Maze Learning, 3' Untranslated Regions, MicroRNAs, Mice, Amyloid Precursor Protein Secretases, Primary Cell Culture
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