Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that affects the cognitive faculties of millions of people worldwide. There is still no known cure for AD, nor a clear understanding of AD etiology. Nevertheless, researchers have made significant strides in understanding various key aspects of AD neuropathology at the cellular and molecular levels. This review is intended to provide a general survey of what is known and unknown, based on the three hallmarks of AD, combined with our knowledge from microRNA research. Our goal is to reevaluate and reassess the current direction of AD research and therapeutic insights, charting a new course and comprehensive plan to combat this imminent global health threat.
Alzheimer’s Association (2016) 2016 Alzheimer’s disease facts and figures. Alzheimers Dement12, 459–509.
2.
JamesBD, LeurgansSE, HebertLE, ScherrPA, YaffeK, BennettDA (2014) Contribution of Alzheimer disease to mortality in the United States. Neurology82, 1045–1050.
3.
ZanettiO, SolerteSB, CantoniF (2009) Life expectancy in Alzheimer’s disease (AD). Arch Gerontol Geriatr49(Suppl 1), 237–243.
4.
ToodayanN (2016) Professor Alois Alzheimer (1864-1915): Lest we forget. J Clin Neurosci31, 47–55.
5.
Lambracht-WashingtonD, RosenbergRN (2013) Advances in the development of vaccines for Alzheimer’s disease. Discov Med15, 319–326.
GentlemanSM, GreenbergBD, SavageMJ, NooriM, NewmanSJ, RobertsGW, GriffinWS, GrahamDI (1997) A beta 42 is the predominant form of amyloid beta-protein in the brains of short-term survivors of head injury. Neuroreport8, 1519–1522.
8.
QiJP, WuH, YangY, WangDD, ChenYX, GuYH, LiuT (2007) Cerebral ischemia and Alzheimer’s disease: The expression of amyloid-beta and apolipoprotein E in human hippocampus. J Alzheimers Dis12, 335–341.
9.
McKeeAC, CantuRC, NowinskiCJ, Hedley-WhyteET, GavettBE, BudsonAE, SantiniVE, LeeHS, KubilusCA, SternRA (2009) Chronic traumatic encephalopathy in athletes: Progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol68, 709–735.
10.
JangSS, ChungHJ (2016) Emerging link between Alzheimer’s disease and homeostatic synaptic plasticity. Neural Plast2016, 7969272.
11.
HaM, KimVN (2014) Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol15, 509–524.
12.
SainiHK, Griffiths-JonesS, EnrightAJ (2007) Genomic analysis of human microRNA transcripts. Proc Natl Acad Sci U S A104, 17719–17724.
13.
RodriguezA, Griffiths-JonesS, AshurstJL, BradleyA (2004) Identification of mammalian microRNA host genes and transcription units. Genome Res14, 1902–1910.
14.
FriedmanRC, FarhKK, BurgeCB, BartelDP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res19, 92–105.
15.
MelamedZ, LevyA, Ashwal-FlussR, Lev-MaorG, MekahelK, AtiasN, GiladS, SharanR, LevyC, KadenerS, AstG (2013) Alternative splicing regulates biogenesis of miRNAs located across exon-intron junctions. Mol Cell50, 869–881.
16.
LewisBP, BurgeCB, BartelDP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell120, 15–20.
17.
ZengY, YiR, CullenBR (2003) MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc Natl Acad Sci U S A100, 9779–9784.
18.
BartelDP (2004) MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell116, 281–297.
O’BrienRJ, WongPC (2011) Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci34, 185–204.
24.
TomitaT (2017) Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease. Adv Biol Regul64, 33–38.
25.
DawkinsE, SmallDH (2014) Insights into the physiological function of the beta-amyloid precursor protein: Beyond Alzheimer’s disease. J Neurochem129, 756–769.
26.
MiloschN, TanrioverG, KunduA, RamiA, FrancoisJC, BaumkotterF, WeyerSW, SamantaA, JaschkeA, BrodF, BuchholzCJ, KinsS, BehlC, MullerUC, KogelD (2014) Holo-APP and G-protein-mediated signaling are required for sAPPalpha-induced activation of the Akt survival pathway. Cell Death Dis5, e1391.
27.
GralleM, BotelhoMG, WoutersFS (2009) Neuroprotective secreted amyloid precursor protein acts by disrupting amyloid precursor protein dimers. J Biol Chem284, 15016–15025.
28.
TurnerPR, O’ConnorK, TateWP, AbrahamWC (2003) Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol70, 1–32.
29.
NorstromE (2017) Metabolic processing of the amyloid precursor protein – new pieces of the Alzheimer’s puzzle. Discov Med23, 269–276.
De StrooperB, KarranE (2016) The cellular phase of Alzheimer’s disease. Cell164, 603–615.
32.
ChowVW, MattsonMP, WongPC, GleichmannM (2010) An overview of APP processing enzymes and products. Neuromolecular Med12, 1–12.
33.
RajendranL, HonshoM, ZahnTR, KellerP, GeigerKD, VerkadeP, SimonsK (2006) Alzheimer’s disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A103, 11172–11177.
34.
CareyRM, BalczBA, Lopez-CoviellaI, SlackBE (2005) Inhibition of dynamin-dependent endocytosis increases shedding of the amyloid precursor protein ectodomain and reduces generation of amyloid beta protein. BMC Cell Biol6, 30.
35.
DelayC, CalonF, MathewsP, HebertSS (2011) Alzheimer-specific variants in the 3’UTR of Amyloid precursor protein affect microRNA function. Mol Neurodegener6, 70.
36.
LongJM, RayB, LahiriDK (2012) MicroRNA-153 physiologically inhibits expression of amyloid-beta precursor protein in cultured human fetal brain cells and is dysregulated in a subset of Alzheimer disease patients. J Biol Chem287, 31298–31310.
37.
LiuCG, WangJL, LiL, XueLX, ZhangYQ, WangPC (2014) MicroRNA-135a and -200b, potential Biomarkers for Alzheimers disease, regulate beta secretase and amyloid precursor protein. Brain Res1583, 55–64.
38.
LiuCG, WangJL, LiL, WangPC (2014) MicroRNA-384 regulates both amyloid precursor protein and beta-secretase expression and is a potential biomarker for Alzheimer’s disease. Int J Mol Med34, 160–166.
39.
LiuCG, SongJ, ZhangYQ, WangPC (2014) MicroRNA-193b is a regulator of amyloid precursor protein in the blood and cerebrospinal fluid derived exosomal microRNA-193b is a biomarker of Alzheimer’s disease. Mol Med Rep10, 2395–2400.
40.
RoyJ, MallickB (2017) Altered gene expression in late-onset Alzheimer’s disease due to SNPs within 3’UTR microRNA response elements. Genomics109, 177–185.
41.
HebertSS, HorreK, NicolaiL, PapadopoulouAS, MandemakersW, SilahtarogluAN, KauppinenS, DelacourteA, De StrooperB (2008) Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A105, 6415–6420.
42.
YangG, SongY, ZhouX, DengY, LiuT, WengG, YuD, PanS (2015) MicroRNA-29c targets beta-site amyloid precursor protein-cleaving enzyme 1 and has a neuroprotective role in vitro and in vivo. Mol Med Rep12, 3081–3088.
43.
WangWX, RajeevBW, StrombergAJ, RenN, TangG, HuangQ, RigoutsosI, NelsonPT (2008) The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. J Neurosci28, 1213–1223.
44.
ZhuHC, WangLM, WangM, SongB, TanS, TengJF, DuanDX (2012) MicroRNA-195 downregulates Alzheimer’s disease amyloid-beta production by targeting BACE1. Brain Res Bull88, 596–601.
45.
KimJ, YoonH, ChungDE, BrownJL, BelmonteKC, KimJ (2016) miR-186 is decreased in aged brain and suppresses BACE1 expression. J Neurochem137, 436–445.
46.
LongJM, RayB, LahiriDK (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 Chem289, 5184–5198.
47.
BarbatoC, PezzolaS, CaggianoC, AntonelliM, FrisoneP, CiottiMT, RubertiF (2014) A lentiviral sponge for miR-101 regulates RanBP9 expression and amyloid precursor protein metabolism in hippocampal neurons. Front Cell Neurosci8, 37.
48.
AugustinR, EndresK, ReinhardtS, KuhnPH, LichtenthalerSF, HansenJ, WurstW, TrumbachD (2012) Computational identification and experimental validation of microRNAs binding to the Alzheimer-related gene ADAM10. BMC Med Genet13, 35.
49.
ChengC, LiW, ZhangZ, YoshimuraS, HaoQ, ZhangC, WangZ (2013) MicroRNA-144 is regulated by activator protein-1 (AP-1) and decreases expression of Alzheimer disease-related a disintegrin and metalloprotease 10 (ADAM10). J Biol Chem288, 13748–13761.
50.
DelayC, DorvalV, FokA, Grenier-BoleyB, LambertJC, HsiungGY, HebertSS (2014) MicroRNAs targeting Nicastrin regulate Abeta production and are affected by target site polymorphisms. Front Mol Neurosci7, 67.
51.
GeekiyanageH, ChanC (2011) MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid beta, novel targets in sporadic Alzheimer’s disease. J Neurosci31, 14820–14830.
52.
BukhariH, GlotzbachA, KolbeK, LeonhardtG, LoosseC, MullerT (2017) Small things matter: Implications of APP intracellular domain AICD nuclear signaling in the progression and pathogenesis of Alzheimer’s disease. Prog Neurobiol156, 189–213.
53.
EbinuJO, YanknerBA (2002) A RIP tide in neuronal signal transduction. Neuron34, 499–502.
54.
ChakrabartiA, MukhopadhyayD (2012) Novel adaptors of amyloid precursor protein intracellular domain and their functional implications. Genomics Proteomics Bioinformatics10, 208–216.
55.
GoodgerZV, RajendranL, TrutzelA, KohliBM, NitschRM, KonietzkoU (2009) Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway. J Cell Sci122, 3703–3714.
56.
KumeH, KametaniF (2006) Abeta 11-40/42 production without gamma-secretase epsilon-site cleavage. Biochem Biophys Res Commun349, 1356–1360.
57.
RobakisNK (2014) Cell signaling abnormalities may drive neurodegeneration in familial Alzheimer disease. Neurochem Res39, 570–575.
58.
SheaYF, ChuLW, ChanAO, HaJ, LiY, SongYQ (2016) A systematic review of familial Alzheimer’s disease: Differences in presentation of clinical features among three mutated genes and potential ethnic differences. J Formos Med Assoc115, 67–75.
59.
ShuR, WongW, MaQH, YangZZ, ZhuH, LiuFJ, WangP, MaJ, YanS, PoloJM, BernardCC, StantonLW, DaweGS, XiaoZC (2015) APP intracellular domain acts as a transcriptional regulator of miR-663 suppressing neuronal differentiation. Cell Death Dis6, e1651.
60.
ZhangW, ThevapriyaS, KimPJ, YuWP, JeHS, TanEK, ZengL (2014) Amyloid precursor protein regulates neurogenesis by antagonizing miR-574-5p in the developing cerebral cortex. Nat Commun5, 3330.
61.
SunX, WuY, GuM, ZhangY (2014) miR-342-5p decreases ankyrin G levels in Alzheimer’s disease transgenic mouse models. Cell Rep6, 264–270.
62.
DengW, AimoneJB, GageFH (2010) New neurons and new memories: How does adult hippocampal neurogenesis affect learning and memory?Nat Rev Neurosci11, 339–350.
63.
BaasPW, QiangL (2005) Neuronal microtubules: When the MAP is the roadblock. Trends Cell Biol15, 183–187.
64.
LeeG, ThangavelR, SharmaVM, LiterskyJM, BhaskarK, FangSM, DoLH, AndreadisA, Van HoesenG, Ksiezak-RedingH (2004) Phosphorylation of tau by fyn: Implications for Alzheimer’s disease. J Neurosci24, 2304–2312.
65.
IqbalK, GongCX, LiuF (2013) Hyperphosphorylation-induced tau oligomers. Front Neurol4, 112.
66.
GuoJL, LeeVM (2013) Neurofibrillary tangle-like tau pathology induced by synthetic tau fibrils in primary neurons over-expressing mutant tau. FEBS Lett587, 717–723.
67.
KleinRL, LinWL, DicksonDW, LewisJ, HuttonM, DuffK, MeyerEM, KingMA (2004) Rapid neurofibrillary tangle formation after localized gene transfer of mutated tau. Am J Pathol164, 347–353.
68.
SarkarS, JunS, RellickS, QuintanaDD, CavendishJZ, SimpkinsJW (2016) Expression of microRNA-34a in Alzheimer’s disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. Brain Res1646, 139–151.
DicksonJR, KruseC, MontagnaDR, FinsenB, WolfeMS (2013) Alternative polyadenylation and miR-34 family members regulate tau expression. J Neurochem127, 739–749.
71.
Santa-MariaI, AlanizME, RenwickN, CelaC, FulgaTA, Van VactorD, TuschlT, ClarkLN, ShelanskiML, McCabeBD, CraryJF (2015) Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau. J Clin Invest125, 681–686.
McLindenKA, TrunovaS, GinigerE (2012) At the fulcrum in health and disease: Cdk5 and the balancing acts of neuronal structure and physiology. Brain Disord Ther2012(Suppl 1), 001.
74.
ShuklaV, SkuntzS, PantHC (2012) Deregulated Cdk5 activity is involved in inducing Alzheimer’s disease. Arch Med Res43, 655–662.
MonciniS, SalviA, ZuccottiP, VieroG, QuattroneA, BarlatiS, De PetroG, VenturinM, RivaP (2011) The role of miR-103 and miR-107 in regulation of CDK5R1 expression and in cellular migration. PLoS One6, e20038.
77.
NelsonPT, WangWX (2010) MiR-107 is reduced in Alzheimer’s disease brain neocortex: Validation study. J Alzheimers Dis21, 75–79.
78.
SunLH, BanT, LiuCD, ChenQX, WangX, YanML, HuXL, SuXL, BaoYN, SunLL, ZhaoLJ, PeiSC, JiangXM, ZongDK, AiJ (2015) Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation. J Neurochem134, 1139–1151.
79.
AbsalonS, KochanekDM, RaghavanV, KrichevskyAM (2013) MiR-26b, upregulated in Alzheimer’s disease, activates cell cycle entry, tau-phosphorylation, and apoptosis in postmitotic neurons. J Neurosci33, 14645–14659.
80.
Banzhaf-StrathmannJ, BenitoE, MayS, ArzbergerT, TahirovicS, KretzschmarH, FischerA, EdbauerD (2014) MicroRNA-125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer’s disease. EMBO J33, 1667–1680.
81.
HaradaT, MorookaT, OgawaS, NishidaE (2001) ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1. Nat Cell Biol3, 453–459.
82.
ChowHM, GuoD, ZhouJC, ZhangGY, LiHF, HerrupK, ZhangJ (2014) CDK5 activator protein p25 preferentially binds and activates GSK3beta. Proc Natl Acad Sci U S A111, E4887–E4895.
XiongYS, LiuFF, LiuD, HuangHZ, WeiN, TanL, ChenJG, ManHY, GongCX, LuY, WangJZ, ZhuLQ (2015) Opposite effects of two estrogen receptors on tau phosphorylation through disparate effects on the miR-218/PTPA pathway. Aging Cell14, 867–877.
85.
KangQ, XiangY, LiD, LiangJ, ZhangX, ZhouF, QiaoM, NieY, HeY, ChengJ, DaiY, LiY (2017) MiR-124-3p attenuates hyperphosphorylation of Tau protein-induced apoptosis via caveolin-1-PI3K/Akt/GSK3beta pathway in N2a/APP695swe cells. Oncotarget8, 24314–24326.
86.
LinG, LiuB, MengZ, LiuY, LiX, WuX, ZhouQ, XuK (2017) MiR-26a enhances invasive capacity by suppressing GSK3beta in human lung cancer cells. Exp Cell Res352, 364–374.
87.
YangHW, LiuGH, LiuYQ, ZhaoHC, YangZ, ZhaoCL, ZhangXF, YeH (2016) Over-expression of microRNA-940 promotes cell proliferation by targeting GSK3beta and sFRP1 in human pancreatic carcinoma. Biomed Pharmacother83, 593–601.
88.
LiZ, XuZ, XieQ, GaoW, XieJ, ZhouL (2016) miR-1303 promotes the proliferation of neuroblastoma cell SH-SY5Y by targeting GSK3beta and SFRP1. Biomed Pharmacother83, 508–513.
89.
QiuHJ, LuXH, YangSS, WengCY, ZhangEK, ChenFC (2016) MiR-769 promoted cell proliferation in human melanoma by suppressing GSK3B expression. Biomed Pharmacother82, 117–123.
90.
JiangJJ, LiuCM, ZhangBY, WangXW, ZhangM, Saijilafu, ZhangSR, HallP, HuYW, ZhouFQ (2015) MicroRNA-26a supports mammalian axon regeneration in vivo by suppressing GSK3beta expression. Cell Death Dis6, e1865.
91.
LiuW, ZhaoJ, LuG (2016) miR-106b inhibits tau phosphorylation at Tyr18 by targeting Fyn in a model of Alzheimer’s disease. Biochem Biophys Res Commun478, 852–857.
92.
DyerAH, VahdatpourC, SanfeliuA, TropeaD (2016) The role of Insulin-Like Growth Factor 1 (IGF-1) in brain development, maturation and neuroplasticity. Neuroscience325, 89–99.
KarranE, MerckenM, De StrooperB (2011) The amyloid cascade hypothesis for Alzheimer’s disease: An appraisal for the development of therapeutics. Nat Rev Drug Discov10, 698–712.
95.
MusiekES, HoltzmanDM (2015) Three dimensions of the amyloid hypothesis: Time, space and ‘wingmen’. Nat Neurosci18, 800–806.
96.
TayebHO, MurrayED, PriceBH, TaraziFI (2013) Bapineuzumab and solanezumab for Alzheimer’s disease: Is the ‘amyloid cascade hypothesis’ still alive?Expert Opin Biol Ther13, 1075–1084.
97.
OvchinnikovDA, KornO, VirshupI, WellsCA, WolvetangEJ (2018) The impact of APP on Alzheimer-like pathogenesis and gene expression in Down syndrome iPSC-derived neurons. Stem Cell Reports11, 32–42.
98.
SperlingRA, JackCRJr, AisenPS (2011) Testing the right target and right drug at the right stage. Sci Transl Med3, 111cm133.
99.
SelkoeDJ (2002) Alzheimer’s disease is a synaptic failure. Science298, 789–791.
100.
McDadeE, BatemanRJ (2017) Stop Alzheimer’s before it starts. Nature547, 153–155.
101.
JahnH (2013) Memory loss in Alzheimer’s disease. Dialogues Clin Neurosci15, 445–454.
102.
AdlamAL, BozeatS, ArnoldR, WatsonP, HodgesJR (2006) Semantic knowledge in mild cognitive impairment and mild Alzheimer’s disease. Cortex42, 675–684.
103.
JoubertS, BrambatiSM, AnsadoJ, BarbeauEJ, FelicianO, DidicM, LacombeJ, GoldsteinR, ChayerC, KergoatMJ (2010) The cognitive and neural expression of semantic memory impairment in mild cognitive impairment and early Alzheimer’s disease. Neuropsychologia48, 978–988.
104.
MuY, GageFH (2011) Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol Neurodegener6, 85.
105.
NevesG, CookeSF, BlissTV (2008) Synaptic plasticity, memory and the hippocampus: A neural network approach to causality. Nat Rev Neurosci9, 65–75.
106.
MayfordM, SiegelbaumSA, KandelER (2012) Synapses and memory storage. Cold Spring Harb Perspect Biol4, pii:a005751.
107.
BlissTV, LomoT (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol232, 331–356.
108.
SweattJD (1999) Toward a molecular explanation for long-term potentiation. Learn Mem6, 399–416.
109.
NicollRA (2017) A brief history of long-term potentiation. Neuron93, 281–290.
110.
HardtO, NaderK, WangYT (2014) GluA2-dependent AMPA receptor endocytosis and the decay of early and late long-term potentiation: Possible mechanisms for forgetting of short- and long-term memories. Philos Trans R Soc Lond B Biol Sci369, 20130141.
111.
AbrahamWC, LoganB, GreenwoodJM, DragunowM (2002) Induction and experience-dependent consolidation of stable long-term potentiation lasting months in the hippocampus. J Neurosci22, 9626–9634.
112.
KelleherRJ3rd, GovindarajanA, TonegawaS (2004) Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron44, 59–73.
113.
KangH, SchumanEM (1996) A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science273, 1402–1406.
114.
PanjaD, BramhamCR (2014) BDNF mechanisms in late LTP formation: A synthesis and breakdown. Neuropharmacology76(Pt C), 664–676.
115.
AlberiniCM (2009) Transcription factors in long-term memory and synaptic plasticity. Physiol Rev89, 121–145.
116.
PlattSR (2007) The role of glutamate in central nervous system health and disease–a review. Vet J173, 278–286.
117.
LismanJ, YasudaR, RaghavachariS (2012) Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci13, 169–182.
AscherP, NowakL (1988) The role of divalent cations in the N-methyl-D-aspartate responses of mouse central neurones in culture. J Physiol399, 247–266.
120.
HerringBE, NicollRA (2016) Long-term potentiation: From CaMKII to AMPA Receptor trafficking. Annu Rev Physiol78, 351–365.
121.
WaymanGA, LeeYS, TokumitsuH, SilvaAJ, SoderlingTR (2008) Calmodulin-kinases: Modulators of neuronal development and plasticity. Neuron59, 914–931.
122.
LiaoGY, WagnerDA, HsuMH, LeonardJP (2001) Evidence for direct protein kinase-C mediated modulation of N-methyl-D-aspartate receptor current. Mol Pharmacol59, 960–964.
123.
AhmedR, ZhaXM, GreenSH, DaileyME (2006) Synaptic activity and F-actin coordinately regulate CaMKIIalpha localization to dendritic postsynaptic sites in developing hippocampal slices. Mol Cell Neurosci31, 37–51.
124.
RenSQ, YanJZ, ZhangXY, BuYF, PanWW, YaoW, TianT, LuW (2013) PKClambda is critical in AMPA receptor phosphorylation and synaptic incorporation during LTP. EMBO J32, 1365–1380.
125.
CaldeiraMV, MeloCV, PereiraDB, CarvalhoR, CorreiaSS, BackosDS, CarvalhoAL, EstebanJA, DuarteCB (2007) Brain-derived neurotrophic factor regulates the expression and synaptic delivery of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunits in hippocampal neurons. J Biol Chem282, 12619–12628.
126.
WuK, LenGW, McAuliffeG, MaC, TaiJP, XuF, BlackIB (2004) Brain-derived neurotrophic factor acutely enhances tyrosine phosphorylation of the AMPA receptor subunit GluR1 via NMDA receptor-dependent mechanisms. Brain Res Mol Brain Res130, 178–186.
127.
LuscherC, MalenkaRC (2012) NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb Perspect Biol4, pii:a00571.
128.
KandelER (2012) The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain5, 14.
NaES, NelsonED, KavalaliET, MonteggiaLM (2013) The impact of MeCP2 loss- or gain-of-function on synaptic plasticity. Neuropsychopharmacology38, 212–219.
131.
NaES, NelsonED, AdachiM, AutryAE, MahgoubMA, KavalaliET, MonteggiaLM (2012) A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission. J Neurosci32, 3109–3117.
132.
KonopkaW, KirykA, NovakM, HerwerthM, ParkitnaJR, WawrzyniakM, KowarschA, MichalukP, DzwonekJ, ArnspergerT, WilczynskiG, MerkenschlagerM, TheisFJ, KohrG, KaczmarekL, SchutzG (2010) MicroRNA loss enhances learning and memory in mice. J Neurosci30, 14835–14842.
133.
RajasethupathyP, FiumaraF, SheridanR, BetelD, PuthanveettilSV, RussoJJ, SanderC, TuschlT, KandelE (2009) Characterization of small RNAs in Aplysia reveals a role for miR-124 in constraining synaptic plasticity through CREB. Neuron63, 803–817.
134.
BartschD, CasadioA, KarlKA, SerodioP, KandelER (1998) CREB1 encodes a nuclear activator, a repressor, and a cytoplasmic modulator that form a regulatory unit critical for long-term facilitation. Cell95, 211–223.
ScottHL, TamagniniF, NarduzzoKE, HowarthJL, LeeYB, WongLF, BrownMW, WarburtonEC, BashirZI, UneyJB (2012) MicroRNA-132 regulates recognition memory and synaptic plasticity in the perirhinal cortex. Eur J Neurosci36, 2941–2948.
146.
KleinME, LioyDT, MaL, ImpeyS, MandelG, GoodmanRH (2007) Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat Neurosci10, 1513–1514.
147.
HuXM, CaoSB, ZhangHL, LyuDM, ChenLP, XuH, PanZQ, ShenW (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 Pain12, 1744806916666283.
148.
WangJ, XuW, ShaoJ, HeZ, DingZ, HuangJ, GuoQ, ZouW (2017) miR-219-5p targets CaMKIIgamma to attenuate morphine tolerance in rats. Oncotarget8, 28203–28214.
149.
XuY, ChenP, WangX, YaoJ, ZhuangS (2018) miR-34a deficiency in APP/PS1 mice promotes cognitive function by increasing synaptic plasticity via AMPA and NMDA receptors. Neurosci Lett670, 94–104.
150.
GaoJ, WangWY, MaoYW, GraffJ, GuanJS, PanL, MakG, KimD, SuSC, TsaiLH (2010) A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature466, 1105–1109.
151.
SchonrockN, HumphreysDT, PreissT, GotzJ (2012) Target gene repression mediated by miRNAs miR-181c and miR-9 both of which are down-regulated by amyloid-beta. J Mol Neurosci46, 324–335.
LiuCM, WangRY, Saijilafu, JiaoZX, ZhangBY, ZhouFQ (2013) MicroRNA-138 and SIRT1 form a mutual negative feedback loop to regulate mammalian axon regeneration. Genes Dev27, 1473–1483.
155.
GuQH, YuD, HuZ, LiuX, YangY, LuoY, ZhuJ, LiZ (2015) miR-26a and miR-384-5p are required for LTP maintenance and spine enlargement. Nat Commun6, 6789.
156.
BedecarratsA, ChenS, PearceK, CaiD, GlanzmanDL (2018) RNA from trained Aplysia can induce an epigenetic engram for long-term sensitization in untrained Aplysia. eNeuro5, ENEURO.003818.2018.
157.
FischerA, SananbenesiF, SchrickC, SpiessJ, RadulovicJ (2002) Cyclin-dependent kinase 5 is required for associative learning. J Neurosci22, 3700–3707.
158.
JianC, LuM, ZhangZ, LiuL, LiX, HuangF, XuN, QinL, ZhangQ, ZouD (2017) miR-34a knockout attenuates cognitive deficits in APP/PS1 mice through inhibition of the amyloidogenic processing of APP. Life Sci182, 104–111.
159.
RangarajuV, Tom DieckS, SchumanEM (2017) Local translation in neuronal compartments: How local is local?EMBO Rep18, 693–711.
160.
Fernandez-MoyaSM, BauerKE, KieblerMA (2014) Meet the players: Local translation at the synapse. Front Mol Neurosci7, 84.
161.
FreyU, MorrisRG (1997) Synaptic tagging and long-term potentiation. Nature385, 533–536.
MeydanC, Shenhar-TsarfatyS, SoreqH (2016) MicroRNA regulators of anxiety and metabolic disorders. Trends Mol Med22, 798–812.
168.
CarrickWT, BurksB, CairnsMJ, KocerhaJ (2016) Noncoding RNA regulation of dopamine signaling in diseases of the central nervous system. Front Mol Biosci3, 69.
169.
DreyerJL (2010) New insights into the roles of microRNAs in drug addiction and neuroplasticity. Genome Med2, 92.
170.
BarbieratoM, ZussoM, SkaperSD, GiustiP (2015) MicroRNAs: Emerging role in the endogenous mu opioid system. CNS Neurol Disord Drug Targets14, 239–250.
171.
LeeK, KimH, AnK, KwonOB, ParkS, ChaJH, KimMH, LeeY, KimJH, ChoK, KimHS (2016) Replenishment of microRNA-188-5p restores the synaptic and cognitive deficits in 5XFAD mouse model of Alzheimer’s disease. Sci Rep6, 34433.
172.
SchochKM, MillerTM (2017) Antisense oligonucleotides: Translation from mouse models to human neurodegenerative diseases. Neuron94, 1056–1070.
173.
DeVosSL, MillerRL, SchochKM, HolmesBB, KebodeauxCS, WegenerAJ, ChenG, ShenT, TranH, NicholsB, ZanardiTA, KordasiewiczHB, SwayzeEE, BennettCF, DiamondMI, MillerTM (2017) Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med9, eaag0481.
174.
FarrSA, EricksonMA, NiehoffML, BanksWA, MorleyJE (2014) Central and peripheral administration of antisense oligonucleotide targeting amyloid-beta protein precursor improves learning and memory and reduces neuroinflammatory cytokines in Tg2576 (AbetaPPswe) mice. J Alzheimers Dis40, 1005–1016.
175.
WangX, LiuP, ZhuH, XuY, MaC, DaiX, HuangL, LiuY, ZhangL, QinC (2009) miR-34a, a microRNA up-regulated in a double transgenic mouse model of Alzheimer’s disease, inhibits bcl2 translation. Brain Res Bull80, 268–273.
176.
MatsunagaS, KishiT, IwataN (2015) Memantine monotherapy for Alzheimer’s disease: A systematic review and meta-analysis. PLoS One10, e0123289.
