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Theranostics 2023; 13(9):3021-3040. doi:10.7150/thno.81826 This issue Cite

Research Paper

Decreased miR-451a in cerebrospinal fluid, a marker for both cognitive impairment and depressive symptoms in Alzheimer's disease

Hu Feng^1,2, Panpan Hu^1,3, Yan Chen^1,2, Huaiqing Sun^1,4, Jiachen Cai^1,2, Xiaoxin He^1,2, Qiuchen Cao¹, Mengmei Yin^1,4, Yanli Zhang^1,2, Qian Li^1,2, Junying Gao^1,2, Charles Marshall⁵, Chengyu Sheng^1,2, Jingping Shi^2,6✉, Ming Xiao^1,2✉

1. Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China.
2. Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China.
3. Department of Anesthetic Pharmacology, Faculty of Anesthesiology, Naval Medical University, Shanghai, 200082, China.
4. Department of Neurology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
5. Alice Lloyd College, Pippa Passes, KY, USA.
6. Department of Neurology, the Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, 210029, China.

✉ Corresponding authors: Jingping Shi, jingping_scom; Ming Xiao, mingxedu.cn.

Abstract

Background: Alzheimer's disease (AD) patients are often accompanied by depressive symptoms, but its underlying mechanism remains unclear. The present study aimed to explore the potential role of microRNAs in the comorbidity of AD and depression.

Methods: The miRNAs associated with AD and depression were screened from databases and literature and then confirmed in the cerebrospinal fluid (CSF) of AD patients and different ages of transgenic APP/PS1 mice. AAV9-miR-451a-GFP was injected into the medial prefrontal cortex (mPFC) of APP/PS1 mice at seven months, and four weeks later, a series of behavioral and pathological analyses were performed.

Results: AD patients had low CSF levels of miR-451a, which was positively correlated with the cognitive assessment score, but negatively with their depression scale. In the mPFC of APP/PS1 transgenic mice, the miR-451a levels also decreased significantly in the neurons and microglia. Specific virus vector-induced overexpression of miR-451a in the mPFC of APP/PS1 mice ameliorated AD-related behavior deficits and pathologies, including long-term memory defects, depression-like phenotype, β-amyloid load, and neuroinflammation. Mechanistically, miR-451a decreased the expression of neuronal β-secretase 1 of neurons through inhibiting Toll-like receptor 4/Inhibitor of kappa B Kinase β/ Nuclear factor kappa-B signaling pathway and microglial activation by inhibiting activation of NOD-like receptor protein 3, respectively.

Conclusion: This finding highlighted miR-451a as a potential target for diagnosing and treating AD, especially for those with coexisting symptoms of depression.

Keywords: Alzheimer's disease, miR-451a, BACE1, depression, medial prefrontal cortex

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