Epigenetic Regulation of Amyloid-beta Metabolism in Alzheimer’s Disease

Abstract

Senile plaques (SPs) are one of the pathological features of Alzheimer’s disease (AD) and they are formed by the overproduction and aggregation of amyloid-beta (Aβ) peptides derived from the abnormal cleavage of amyloid precursor protein (APP). Thus, understanding the regulatory mechanisms during Aβ metabolism is of great importance to elucidate AD pathogenesis. Recent studies have shown that epigenetic modulation—including DNA methylation, non-coding RNA alterations, and histone modifications—is of great significance in regulating Aβ metabolism. In this article, we review the aberrant epigenetic regulation of Aβ metabolism.

Keywords

Alzheimer’s disease / amyloid-β / epigenetics / DNA methylation / microRNAs / histone modifications

References

[1] 2016 Alzheimer’s disease facts and figures. Alzheimers Dement, 2016,12(4):459–509

[2] HaneFT, LeeBY, LeonenkoZ. Recent Progress in Alzheimer’s Disease Research, Part 1: Pathology. J Alzheimer Dis, 2017, 57(1): 1-28

[3] BallardC, GauthierS, CorbettA, et al.. Alzheimer’s disease. Lancet, 2011, 377(10): 1019-1031

[4] BergerSL, KouzaridesT, ShiekhattarR, et al.. An operational definition of epigenetics. Genes Dev, 2009, 23(7): 781-783

[5] BrunetA, BergerSL. Epigenetics of aging and aging-related disease. J Gerontol A Biol Sci Med Sci, 2014, 69(Suppl 1): S17-S20

[6] HollingworthP, HaroldD, JonesL, et al.. Alzheimer’s disease genetics: current knowledge and future challenges. Int J Geriatr Psychiatry, 2011, 26(8): 793-802

[7] MiglioreL, CoppedeF. Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases. Mutat Res, 2009, 667(1–2): 82-97

[8] DawsonMA, KouzaridesT. Cancer epigenetics: from mechanism to therapy. Cell, 2012, 150(1): 12-27

[9] van DijkSJ, MolloyPL, VarinliH, et al.. Epigenetics and human obesity. Int J Obes (Lond), 2015, 39(1): 85-97

[10] ChenGF, XuTH, YanY, et al.. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin, 2017, 38(9): 1205-1235

[11] LudewigS, KorteM. Novel Insights into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity. Front Mol Neurosci, 2016, 9(9): 161

[12] WascoW, GurubhagavatulaS, ParadisMD, et al.. Isolation and characterization of APLP2 encoding a homologue of the Alzheimer’s associated amyloid beta protein precursor. Nat Genet, 1993, 5(1): 95-100

[13] YoshikaiS, SasakiH, Doh-uraK, et al.. Genomic organization of the human amyloid beta-protein precursor gene. Gene, 1990, 87(2): 257-263

[14] HussainI, PowellD, HowlettDR, et al.. Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci, 1999, 14(6): 419-427

[15] NicolasM, HassanBA. Amyloid precursor protein and neural development. Development (Cambridge, England), 2014, 141(13): 2543-2548

[16] BarrachinaM, FerrerI. DNA methylation of Alzheimer disease and tauopathy-related genes in postmortem brain. J Neuropathol Exp Neurol, 2009, 68(8): 880-891

[17] QaziTJ, QuanZ, MirA, et al.. Epigenetics in Alzheimer’s Disease: Perspective of DNA Methylation. Mol Neurobiol, 2018, 55(2): 1026-1044

[18] Delgado-MoralesR, EstellerM. Opening up the DNA methylome of dementia. Mol Psychiatry, 2017, 22(4): 485-496

[19] MastroeniD, McKeeA, GroverA, et al.. Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer’s disease. PLoS One, 2009, 4(8): e6617

[20] MastroeniD, GroverA, DelvauxE, et al.. Epigenetic changes in Alzheimer’s disease: decrements in DNA methylation. Neurobiol Aging, 2010, 31(12): 2025-2037

[21] ChouliarasL, MastroeniD, DelvauxE, et al.. Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer’s disease patients. Neurobiol Aging, 2013, 34(9): 2091-2099

[22] TohgiH, UtsugisawaK, NaganeY, et al.. Reduction with age in methylcytosine in the promoter region −224 approximately −101 of the amyloid precursor protein gene in autopsy human cortex. Brain Res Mol Brain Res, 1999, 70(2): 288-292

[23] WestRL, LeeJM, MarounLE. Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer’s disease patient. J Mol Neurosci, 1995, 6(2): 141-146

[24] HouY, ChenH, HeQ, et al.. Changes in methylation patterns of multiple genes from peripheral blood leucocytes of Alzheimer’s disease patients. Acta Neuropsychiatr, 2013, 25(2): 66-76

[25] IwataA, NagataK, HatsutaH, et al.. Altered CpG methylation in sporadic Alzheimer’s disease is associated with APP and MAPT dysregulation. Hum Mol Genet, 2014, 23(3): 648-656

[26] ByunCJ, SeoJ, JoSA, et al.. DNA methylation of the 5′-untranslated region at +298 and +351 represses BACE1 expression in mouse BV-2 microglial cells. Biochem Biophys Res Commun, 2012, 417(1): 387-392

[27] CordnerZA, TamashiroKL. Effects of chronic variable stress on cognition and Bace1 expression among wild-type mice. Transl Psychiatry, 2016, 6(7): e854

[28] LiP, MarshallL, OhG, et al.. Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer’s disease pathology and cognitive symptoms. Nat Commun, 2019, 10(1): 2246

[29] MarrRA, GuanH, RockensteinE, et al.. Neprilysin regulates amyloid Beta peptide levels. J Mol Neurosci, 2004, 22(1–2): 5-11

[30] MarrRA, RockensteinE, MukherjeeA, et al.. Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. J Neurosci, 2003, 23(6): 1992-1996

[31] MaruyamaM, HiguchiM, TakakiY, et al.. Cerebrospinal fluid neprilysin is reduced in prodromal Alzheimer’s disease. Ann Neurol, 2005, 57(6): 832-842

[32] ChenKL, WangSS, YangYY, et al.. The epigenetic effects of amyloid-beta(1–40) on global DNA and neprilysin genes in murine cerebral endothelial cells. Biochem Biophys Res Commun, 2009, 378(1): 57-61

[33] NagataK, ManoT, MurayamaS, et al.. DNA methylation level of the neprilysin promoter in Alzheimer’s disease brains. Neurosci Lett, 2018, 670(3): 8-13

[34] DengY, LuX, WangL, et al.. Curcumin inhibits the AKT/NF-κB signaling via CpG demethylation of the promoter and restoration of NEP in the N2a cell line. Aaps J, 2014, 16(4): 649-657

[35] SerotJM, ChristmannD, DubostT, et al.. CSF-folate levels are decreased in late-onset AD patients. J Neural Transm (Vienna), 2001, 108(1): 93-99

[36] GrossiE, StoccoroA, TannorellaP, et al.. Artificial Neural Networks Link One-Carbon Metabolism to Gene-Promoter Methylation in Alzheimer’s Disease. J Alzheimers Dis, 2016, 53(4): 1517-1522

[37] LiW, LiuH, YuM, et al.. Folic acid administration inhibits amyloid beta-peptide accumulation in APP/PS1 transgenic mice. J Nutr Biochem, 2015, 26(8): 883-891

[38] Do CarmoS, HanzelCE, JacobsML, et al.. Rescue of Early bace-1 and Global DNA Demethylation by S-Adenosylmethionine Reduces Amyloid Pathology and Improves Cognition in an Alzheimer’s Model. Sci Rep, 2016, 6(10): 34051

[39] FusoA, SeminaraL, CavallaroRA, et al.. S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Mol Cell Neurosci, 2005, 28(1): 195-204

[40] ScarpaS, FusoA, D’AnselmiF, et al.. Presenilin 1 gene silencing by S-adenosylmethionine: a treatment for Alzheimer disease?. FEBS Lett, 2003, 541(1–3): 145-148

[41] LiuY, WangM, MarcoraEM, et al.. Promoter DNA hypermethylation — Implications for Alzheimer’s disease. Neurosci Lett, 2019, 711: 134403

[42] Blanco-LuquinI, AltunaM, Sánchez-Ruiz de GordoaJ, et al.. PLD3 epigenetic changes in the hippocampus of Alzheimer’s disease. Clin Epigenetics, 2018, 10(1): 116

[43] ForakerJ, MillardSP, LeongL, et al.. The APOE Gene is Differentially Methylated in Alzheimer’s Disease. J Alzheimers Dis, 2015, 48(3): 745-755

[44] FerriE, ArosioB, D’AddarioC, et al.. Gene promoter methylation and expression of Pin1 differ between patients with frontotemporal dementia and Alzheimer’s disease. J Neurol Sci, 2016, 362: 283-286

[45] HodgsonN, TrivediM, MuratoreC, et al.. Soluble oligomers of amyloid-beta cause changes in redox state, DNA methylation, and gene transcription by inhibiting EAAT3 mediated cysteine uptake. J Alzheimers Dis, 2013, 36(1): 197-209

[46] HuoZ, ZhuY, YuL, et al.. DNA methylation variability in Alzheimer’s disease. Neurobiol Aging, 2019, 76: 35-44

[47] Idda ML, Munk R, Abdelmohsen K, et al. Noncoding RNAs in Alzheimer’s disease. Wiley Interdiscip Rev RNA, 2018,9 (2): https://doi.org/10.1002/wrna.1463

[48] KikoT, NakagawaK, TsudukiT, et al.. MicroRNAs in plasma and cerebrospinal fluid as potential markers for Alzheimer’s disease. J Alzheimers Dis, 2014, 39(2): 253-259

[49] Di MecoA, PraticoD. MicroRNAs as Therapeutic Targets for Alzheimer’s Disease. J Alzheimers Dis, 2016, 53(2): 367-372

[50] AmakiriN, KubosumiA, TranJ, et al.. Amyloid Beta and MicroRNAs in Alzheimer’s Disease. Front Neurosci, 2019, 13: 430

[51] LiuHY, FuX, LiYF, et al.. miR-15b-5p targeting amyloid precursor protein is involved in the anti-amyloid eflect of curcumin in swAPP695-HEK293 cells. Neural Regen Res, 2019, 14(9): 1603-1609

[52] LongJM, MaloneyB, RogersJT, et al.. Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5′-untranslated region: Implications in Alzheimer’s disease. Mol Psychiatry, 2019, 24(3): 345-363

[53] EndresK, DellerT. Regulation of Alpha-Secretase ADAM10 In vitro and In vitro: Genetic, Epigenetic, and Protein-Based Mechanisms. Front Mol Neurosci, 2017, 10: 56

[54] ManzinePR, PelucchiS, HorstMA, et al.. microRNA 221 Targets ADAM10 mRNA and is Downregulated in Alzheimer’s Disease. J Alzheimers Dis, 2018, 61(1): 113-123

[55] JianC, LuM, ZhangZ, et al.. miR-34a knockout attenuates cognitive deficits in APP/PS1 mice through inhibition of the amyloidogenic processing of APP. Life Sci, 2017, 182: 104-111

[56] HernandezrappJ, RainoneS, GoupilC, et al.. microRNA-132/212 deficiency enhances Aβ production and senile plaque deposition in Alzheimer’s disease triple transgenic mice. Sci Rep, 2016, 6: 30953

[57] FuL, JiangG, WengH, et al.. Cerebrovascular miRNAs correlate with the clearance of Aβ through perivascular route in younger 3xTg-AD mice. Brain Pathol, 2020, 30(1): 92-105

[58] LongJM, RayB, LahiriDK. MicroRNA-339-5p Down-regulates Protein Expression of β-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, 2014, 289(8): 5184

[59] FaghihiMA, ZhangM, HuangJ, et al.. Evidence for natural antisense transcript-mediated inhibition of microRNA function. Genome Biol, 2010, 11(5): R56

[60] ZhongZ, YuanK, TongX, et al.. MiR-16 attenuates β-amyloid-induced neurotoxicity through targeting β-site amyloid precursor protein-cleaving enzyme 1 in an Alzheimer’s disease cell model. Neuroreport, 2018, 29(16): 1365-1372

[61] WangL, LiuJ, WangQ, et al.. MicroRNA-200a-3p Mediates Neuroprotection in Alzheimer-Related Deficits and Attenuates Amyloid-Beta Overproduction and Tau Hyperphosphorylation Coregulating BACE1 and PRKACB. Front Pharmacol, 2019, 10: 806

[62] QianQ, ZhangJ, HeFP, et al.. Down-regulated expression of microRNA-338-5p contributes to neuropathology in Alzheimer’s disease. Faseb J, 2019, 33(3): 4404-4417

[63] HigakiS, MuramatsuM, MatsudaA, et al.. Defensive effect of microRNA-200b/c against amyloid-beta peptide-induced toxicity in Alzheimer’s disease models. PLoS One, 2018, 13(5): e0196929

[64] ChenFZ, ZhaoY, ChenHZ. MicroRNA-98 reduces amyloid β-protein production and improves oxidative stress and mitochondrial dysfunction through the Notch signaling pathway via HEY2 in Alzheimer’s disease mice. Int J Mol Med, 2019, 43(1): 91-102

[65] ZhouY, WangZF, LiW, et al.. Protective effects of microRNA-330 on amyloid β-protein production, oxidative stress, and mitochondrial dysfunction in Alzheimer’s disease by targeting VAV1 via the MAPK signaling pathway. J Cell Biochem, 2018, 119(7): 5437-5448

[66] HuYK, WangX, LiL, et al.. MicroRNA-98 induces an Alzheimer’s disease-like disturbance by targeting insulin-like growth factor 1. Neurosci Bull, 2013, 29(6): 745-751

[67] LiuH, TianT, QinS, et al.. Folic acid deficiency enhances abeta accumulation in APP/PS1 mice brain and decreases amyloid-associated miRNAs expression. J Nutr Biochem, 2015, 26(12): 1502-1508

[68] LiuT, HuangY, ChenJ, et al.. Attenuated ability of BACE1 to cleave the amyloid precursor protein via silencing long noncoding RNA BACE1AS expression. Mol Med Rep, 2014, 10(3): 1275-1281

[69] FaghihiMA, ModarresiF, KhalilAM, et al.. Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretase. Nat Med, 2008, 14(7): 723-730

[70] MassoneS, CiarloE, VellaS, et al.. NDM29, a RNA polymerase III-dependent non coding RNA, promotes amyloidogenic processing of APP and amyloid beta secretion. Biochimica et biophysica acta, 2012, 1823(7): 1170-1177

[71] CiarloE, MassoneS, PennaI, et al.. An intronic ncRNA-dependent regulation of SORL1 expression affecting Abeta formation is upregulated in post-mortem Alzheimer’s disease brain samples. Dis Model Mech, 2013, 6(2): 424-433

[72] ShiZ, ChenT, YaoQ, et al.. The circular RNA ciRS-7 promotes APP and BACE1 degradation in an NF-κB-dependent manner. Febs J, 2017, 284(7): 1096-1109

[73] ZhaoMY, WangGQ, WangNN, et al.. The long-non-coding RNA NEAT1 is a novel target for Alzheimer’s disease progression via miR-124/BACE1 axis. Neurol Res, 2019, 41(6): 489-497

[74] RodaAR, Montoliu-gayaL, VillegasS. The Role of Apolipoprotein E Isoforms in Alzheimer’s Disease. J Alzheimers Dis, 2019, 68(2): 459-471

[75] KoldamovaR, FitzNF, LefterovI. ATP-binding cassette transporter A1: from metabolism to neurodegeneration. Neurobiol Dis, 2014, 72(PtA): 13-21

[76] KimJ, YoonH, RamírezCM, et al.. MiR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression. Exp Neurol, 2012, 235(2): 476-483

[77] KimJ, YoonH, HorieT, et al.. microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain. J Neurosci, 2015, 35(44): 14717-14726

[78] WangZ, QinW, WeiCB, et al.. The microRNA-1908 up-regulation in the peripheral blood cells impairs amyloid clearance by targeting ApoE. Int J Geriatr Psychiatry, 2018, 33(7): 980-986

[79] FengCZ, YinJB, YangJJ, et al.. Regulatory factor X1 depresses ApoE-dependent Aβ uptake by miRNA-124 in microglial response to oxidative stress. Neuroscience, 2017, 344: 217-228

[80] Fernández-de, FrutosM, Galán-chiletI, GoedekeL, et al.. MicroRNA 7 Impairs Insulin Signaling and Regulates Aβ Levels through Posttranscriptional Regulation of the Insulin Receptor Substrate 2, Insulin Receptor, Insulin-Degrading Enzyme, and Liver X Receptor Pathway. Mol Cell Biol, 2019, 39(22): e00170-19

[81] WangZ, ZhaoY, XuN, et al.. NEAT1 regulates neuroglial cell mediating Aβ clearance via the epigenetic regulation of endocytosis-related genes expression. Cell Mol Life Sci: CMLS, 2019, 76(15): 3005-3018

[82] TiribuziR, CrispoltoniL, PorcellatiS, et al.. miR128 up-regulation correlates with impaired amyloid β(1–42) degradation in monocytes from patients with sporadic Alzheimer’s disease. Neurobiol Aging, 2014, 35(2): 345-356

[83] ZhangC, LuJ, LiuB, et al.. Primate-specific miR-603 is implicated in the risk and pathogenesis of Alzheimer’s disease. Aging, 2016, 8(2): 272-290

[84] Weldon FurrJ, Morales-ScheihingD, ManwaniB, et al.. Cerebral Amyloid Angiopathy, Alzheimer’s Disease and MicroRNA: miRNA as Diagnostic Biomarkers and Potential Therapeutic Targets. Neuromolecular Med, 2019, 21(4): 369-390

[85] AnsariA, MaffiolettiE, MilanesiE, et al.. miR-146a and miR-181a are involved in the progression of mild cognitive impairment to Alzheimer’s disease. Neurobiol Aging, 2019, 82: 102-109

[86] Manzano-CrespoM, AtienzaM, CanteroJL. Lower serum expression of miR-181c-5p is associated with increased plasma levels of amyloid-beta 1–40 and cerebral vulnerability in normal aging. Transl Neurodegener, 2019, 8: 34

[87] ChoiSI, LeeB, WooJH, et al.. APP processing and metabolism in corneal fibroblasts and epithelium as a potential biomarker for Alzheimer’s disease. Exp Eye Res, 2019, 182: 167-174

[88] FischerA, SananbenesiF, MungenastA, et al.. Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharmacol Sci, 2010, 31(12): 605-617

[89] KonsoulaZ, BarileFA. Epigenetic histone acetylation and deacetylation mechanisms in experimental models of neurodegenerative disorders. J Pharmacol Toxicol Methods, 2012, 66(3): 215-220

[90] NarayanP, DragunowM. Alzheimer’s Disease and Histone Code Alterations. Adv Exp Med Biol, 2017, 978: 321-336

[91] YaoZG, LiangL, LiuY, et al.. Valproate improves memory deficits in an Alzheimer’s disease mouse model: investigation of possible mechanisms of action. Cell Mol Neurobiol, 2014, 34(6): 805-812

[92] RicobarazaA, Cuadrado-TejedorM, Pérez-MediavillaA, et al.. Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer’s disease mouse model. Neuropsychopharmacology, 2009, 34(7): 1721-1732

[93] GraffJ, ReiD, GuanJS, et al.. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature, 2012, 483(7388): 222-226

[94] GovindarajanN, RaoP, BurkhardtS, et al.. Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer’s disease. EMBO Mol Med, 2013, 5(1): 52-63

[95] ZhangZY, SchluesenerHJ. Oral administration of histone deacetylase inhibitor MS-275 ameliorates neuroinflammation and cerebral amyloidosis and improves behavior in a mouse model. J Neuropathol Exp Neurol, 2013, 72(3): 178-185

[96] SongJM, SungYM, NamJH, et al.. A Mercaptoacetamide-Based Class II Histone Deacetylase Inhibitor Increases Dendritic Spine Density via RasGRF1/ERK Pathway. J Alzheimers Dis, 2016, 51(2): 591-604

[97] ZhangL, LiuC, WuJ, et al.. Tubastatin A/ACY-1215 improves cognition in Alzheimer’s disease transgenic mice. J Alzheimers Dis, 2014, 41(4): 1193-1205

[98] JanczuraKJ, VolmarCH, SartorGC, et al.. Inhibition of HDAC3 reverses Alzheimer’s disease-related pathologies in vitro and in the 3xTg-AD mouse model. Proc Natl Acad Sci USA, 2018, 115(47): E11148-e11157

[99] VolmarCH, Salah-UddinH, JanczuraKJ, et al.. M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing Alzheimer’s disease genes and improving memory. Proc Natl Acad Sci, 2017, 114(43): E9135-e9144

[100] DubeyH, GulatiK, RayA. Recent studies on cellular and molecular mechanisms in Alzheimer’s disease: focus on epigenetic factors and histone deacetylase. Rev Neurosci, 2018, 29(3): 241-260

[101] PorsteinssonAP, TariotPN, JakimovichLJ, et al.. Valproate therapy for agitation in dementia: open-label extension of a double-blind trial. Am J Geriatr Psychiatry, 2003, 11(4): 434-440

[102] De SimoneA, MilelliA. Histone Deacetylase Inhibitors as Multitarget Ligands: New Players in Alzheimer’s Disease Drug Discovery?. Chem Med Chem, 2019, 14(11): 1067-1073

[103] MarquesSC, LemosR, FerreiroE, et al.. Epigenetic regulation of BACE1 in Alzheimer’s disease patients and in transgenic mice. Neuroscience, 2012, 220: 256-266

[104] LuX, DengY, YuD, et al.. Histone acetyltransferase p300 mediates histone acetylation of PS1 and BACE1 in a cellular model of Alzheimer’s disease. PLoS One, 2014, 9(7): e103067

[105] KumarA, ThakurMK. Epigenetic regulation of presenilin 1 and 2 in the cerebral cortex of mice during development. Dev Neurobiol, 2015, 75(11): 1165-1173

[106] MarziSJ, LeungSK, RibarskaT, et al.. A histone acetylome-wide association study of Alzheimer’s disease identifies disease-associated H3K27ac differences in the entorhinal cortex. Nat Neurosci, 2018, 21(11): 1618-1627

[107] ZhangX, YuY, SunP, et al.. Royal jelly peptides: potential inhibitors of β-secretase in N2a/APP695swe cells. Sci Rep, 2019, 9(1): 168

[108] WangY, HuY, WuZ, et al.. Latent role of in vitro Pb exposure in blocking Aβ clearance and triggering epigenetic modifications. Environ Toxicol Pharmacol, 2019, 66: 14-23

[109] YangJ, LundeLK, NuntagijP, et al.. Loss of astrocyte polarization in the tg-ArcSwe mouse model of Alzheimer’s disease. J Alzheimers Dis, 2011, 27(4): 711-722

[110] ZhangJ, ZhanZ, LiX, et al.. Intermittent Fasting Protects against Alzheimer’s Disease Possible through Restoring Aquaporin-4 Polarity. Front Mol Neurosci, 2017, 10: 395

[111] ZhaoJ, YueD, ZhouY, et al.. The Role of MicroRNAs in Aβ Deposition and Tau Phosphorylation in Alzheimer’s Disease. Front Neurol, 2017, 8: 342