Brain-derived neurotrophic factor (BDNF) is a crucial regulator to support synaptic plasticity and neuronal survival, its significant decrease is a pathophysiological hallmark in Alzheimer’s disease (AD) brains and accounts for poor prognosis. MicroRNAs (miRNAs) interfere with the translation of target mRNAs and control a variety of physiological and pathological processes. MiR-322 is the rodent homologue of human miR-424, it is involved in the modulation of cell differentiation, proliferation, apoptosis and metabolic activities in diverse tissues and organs. However, the roles and potential mechanisms of miR-322 remain elusive in AD pathogenesis. Here we observed miR-322 is significantly increased along with BDNF decrease in AD mouse brain. Bioinformatics prediction implicated that BDNF 3′-untranslated region (3′-UTR) possesses the putative target sequence of miR-322. Luciferase reporter assay identified that miR-322 can directly conjugate to BDNF 3′-UTR. The functional research showed that MiR-322 input deregulates BDNF expression at either mRNA or protein levels, whereas miR-322 silence restores BDNF expression in vitro. Furthermore, we found miR-322 promotes Tau phosphorylation via negatively controlling BDNF–TrkB receptor activation, otherwise MiR-322 silence restores TrkB activation and attenuates tau phosphorylation. Collectively, this study demonstrated a novel miRNA-dependent manner of BDNF degradation in AD pathogenesis, it may drive a miRNAs- or BDNF based therapeutic strategies against Alzheimer’s disease.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Guo T, Noble W, Hanger DP (2017) Roles of tau protein in health and disease. Acta Neuropathol 133(5):665–704
Spires-Jones TL, Attems J, Thal DR (2017) Interactions of pathological proteins in neurodegenerative diseases. Acta Neuropathol 134:187–205
Alves S, Fol R, Cartier N (2016) Gene therapy strategies for Alzheimer’s disease: an overview. Hum Gene Ther 27(2):100–107
McNeill E, Van Vactor D (2012) MicroRNAs shape the neuronal landscape. Neuron 75(3):363–379
Konopka W, Schutz G, Kaczmarek L (2011) The microRNA contribution to learning and memory. Neuroscientist 17(5):468–474
Liu W et al (2012) MicroRNA-16 targets amyloid precursor protein to potentially modulate Alzheimer’s-associated pathogenesis in SAMP8 mice. Neurobiol Aging 33(3):522–534
Hebert SS, Sergeant N, Buee L (2012) MicroRNAs and the regulation of tau metabolism. Int J Alzheimers Dis 2012:406561
Simchovitz A, Heneka MT, Soreq H (2017) Personalized genetics of the cholinergic blockade of neuroinflammation. J Neurochem 142:178–187
Kang Q et al (2017) MiR-124-3p attenuates hyperphosphorylation of tau protein-induced apoptosis via caveolin-1-PI3K/Akt/GSK3beta pathway in N2a/APP695swe cells. Oncotarget 8:24314
Long JM, Ray B, Lahiri DK (2014) MicroRNA-339-5p down-regulates protein expression of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects. J Biol Chem 289(8):5184–5198
Zhang R et al (2016) MiR-195 dependent roles of mitofusin2 in the mitochondrial dysfunction of hippocampal neurons in SAMP8 mice. Brain Res 1652:135–143
Zhao Y, Jaber V, Lukiw WJ (2016) Over-expressed pathogenic miRNAs in Alzheimer’s disease (AD) and prion disease (PrD) drive deficits in TREM2-mediated Abeta42 peptide clearance. Front Aging Neurosci 8:140
Dowdy SF (2017) Overcoming cellular barriers for RNA therapeutics. Nat Biotechnol 35(3):222–229
Millan MJ (2017) Linking deregulation of non-coding RNA to the core pathophysiology of Alzheimer’s disease: an integrative review. Prog Neurobiol 156:1–68
Wen MM (2016) Getting miRNA therapeutics into the target cells for neurodegenerative diseases: a mini-review. Front Mol Neurosci 9:129
Mitre M, Mariga A, Chao MV (2017) Neurotrophin signalling: novel insights into mechanisms and pathophysiology. Clin Sci 131(1):13–23
Criscuolo C et al (2017) Synaptic dysfunction in Alzheimer’s disease and glaucoma: from common degenerative mechanisms toward neuroprotection. Front Cell Neurosci 11:53
Nagahara AH, Tuszynski MH (2011) Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 10(3):209–219
Lu B et al (2013) BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci 14(6):401–416
Faustino C, Rijo P, Reis CP (2017) Nanotechnological strategies for nerve growth factor delivery: Therapeutic implications in Alzheimer’s disease. Pharmacol Res 120:68–87
Yang L, Song S, Lv H (2016) MicroRNA-322 protects hypoxia-induced apoptosis in cardiomyocytes via BDNF gene. Am J Transl Res 8(6):2812–2819
Wang WX et al (2011) Patterns of microRNA expression in normal and early Alzheimer’s disease human temporal cortex: white matter versus gray matter. Acta Neuropathol 121(2):193–205
Alvarez-Mora MI et al (2013) MicroRNA expression profiling in blood from fragile X-associated tremor/ataxia syndrome patients. Genes Brain Behav 12(6):595–603
Rehmsmeier M et al (2004) Fast and effective prediction of microRNA/target duplexes. Rna 10(10):1507–1517
Shen X et al (2016) miR-322/-503 cluster is expressed in the earliest cardiac progenitor cells and drives cardiomyocyte specification. Proc Natl Acad Sci USA 113(34):9551–9556
Gu H et al (2015) The miR-322-TRAF3 circuit mediates the pro-apoptotic effect of high glucose on neural stem cells. Toxicol Sci 144(1):186–196
Berg V et al (2015) miRs-138 and -424 control palmitoylation-dependent CD95-mediated cell death by targeting acyl protein thioesterases 1 and 2 in CLL. Blood 125(19):2948–2957
Rodriguez-Barrueco R et al (2017) miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapy. Genes Dev 31(6):553–566
Ghosh G et al (2010) Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-alpha isoforms and promotes angiogenesis. J Clin Invest 120(11):4141–4154
Chen YC et al (2013) A novel mouse model of atherosclerotic plaque instability for drug testing and mechanistic/therapeutic discoveries using gene and microRNA expression profiling. Circ Res 113(3):252–265
Li L et al (2017) FOXO1-suppressed miR-424 regulates the proliferation and osteogenic differentiation of MSCs by targeting FGF2 under oxidative stress. Sci Rep 7:42331
Gamez B et al (2013) MicroRNA-322 (miR-322) and its target protein Tob2 modulate Osterix (Osx) mRNA stability. J Biol Chem 288(20):14264–14275
Peng S et al (2005) Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J Neurochem 93(6):1412–1421
Boots EA et al (2017) BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer’s Prevention. Neurology 88:2098–2106
Hsiao YH et al (2017) Co-housing reverses memory decline by epigenetic regulation of brain-derived neurotrophic factor expression in an animal model of Alzheimer’s disease. Neurobiol Learn Mem 141:1–8
Bastle RM et al (2017) In silico identification and in vivo validation of miR-495 as a novel regulator of motivation for cocaine that targets multiple addiction-related networks in the nucleus accumbens. Mol Psychiatry 23:434–443
Rahimian P, He JJ (2016) HIV-1 Tat-shortened neurite outgrowth through regulation of microRNA-132 and its target gene expression. J Neuroinflammation 13(1):247
Hu XM et al (2016) Downregulation of miR-219 enhances brain-derived neurotrophic factor production in mouse dorsal root ganglia to mediate morphine analgesic tolerance by upregulating CaMKIIgamma. Mol Pain 12:1744806916666283
Hang P et al (2016) BDNF-mediates down-regulation of microRNA-195 inhibits ischemic cardiac apoptosis in rats. Int J Biol Sci 12(8):979–989
Jaitner C et al (2016) Satb2 determines miRNA expression and long-term memory in the adult central nervous system. Elife. https://doi.org/10.7554/eLife.17361
Tan Y et al (2016) 7,8-Dihydroxyflavone ameliorates cognitive impairment by inhibiting expression of tau pathology in ApoE-knockout mice. Front Aging Neurosci 8:287
Turnbull MT, Coulson EJ (2017) Cholinergic basal forebrain lesion decreases neurotrophin signaling without affecting tau hyperphosphorylation in genetically susceptible mice. J Alzheimers Dis 55(3):1141–1154
Lim YY et al (2016) BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease. Brain 139(Pt 10):2766–2777
Rosa E et al (2016) Tau downregulates BDNF expression in animal and cellular models of Alzheimer’s disease. Neurobiol Aging 48:135–142
Mazzaro N et al (2016) Tau-driven neuronal and neurotrophic dysfunction in a mouse model of early tauopathy. J Neurosci 36(7):2086–2100
Hsiao K et al (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274(5284):99–102
Nobili A et al (2017) Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease. Nat Commun 8:14727
Zhang J et al (2013) Neuroglobin, a novel intracellular hexa-coordinated globin, functions as a tumor suppressor in hepatocellular carcinoma via Raf/MAPK/Erk. Mol Pharmacol 83(5):1109–1119
This project was granted by the Science and Technology Foundation of Guizhou Province (TN2015-60; J-2014-2017) and the National Health and Family Planning Commission of Guizhou Province (WT2017-14).
Conflict of interest
The authors have no relevant financial conflicts of interest to declare.
The Editors have retracted this article following an investigation conducted by the journal. After publication concerns were raised regarding interpretation of the data presented in Fig 4. The Editors requested additional data and clarification to confirm interpretation of data results. After further review, the Editors found that the additional data were not adequate to support the conclusion of the article and that P-values for the additional data were based on improper statistical analyses. With more appropriate statistical analysis, the reported effects for miR-322 and BDNF were not statistically significant. Dr. Chichu Xie agrees to this retraction. None of the other authors have responded to any correspondence from the publisher about this retraction.
About this article
Cite this article
Zhang, J., Liu, Z., Pei, Y. et al. RETRACTED ARTICLE: MicroRNA-322 Cluster Promotes Tau Phosphorylation via Targeting Brain-Derived Neurotrophic Factor. Neurochem Res 43, 736–744 (2018). https://doi.org/10.1007/s11064-018-2475-1
- BDNF–TrkB signal
- Tau phosphorylation
- Alzheimer’s disease