Abstract
Alzheimer’s disease (AD) is a frequent neurodegenerative disorder with progressive neuroinflammation, loss of synaptic plasticity in central neurons and memory deficiency. Numerous studies demonstrated the epigenetic modification of the expression of specific genes involved in the pathogenesis of amyloid-associated memory deficiency. It was also reported that dysregulation of cyclin-dependent kinase 5 (Cdk5) activity critically contributed to the synaptic dysfunction and memory deficiency in the rodent model of AD. The present study aims to study the epigenetic mechanism underlying the altered Cdk5 activity and its functional significance in the rats with hippocampal infusion of amyloid fibrils. Significantly increased mRNA and expression of Cdk5 were observed in the hippocampal CA1 in the rats injected with amyloid fibrils. Increased acetylation of histone H3 was detected in the Cdk5 promoter region in hippocampal CA1 in these rats. Further chromatin immunoprecipitation and bisulfite sequencing studies illustrated the decreased cytosine methylation in the Cdk5 promoter region in hippocampal CA1 in the modeled rats. Administration with Cdk5 inhibitor roscovitine significantly attenuated the phosphorylation of tau, recovered the synaptic dysfunction of hippocampal CA1 neurons, and improved the behavioral performance in the Morris water maze test and novel object recognition test in the rats injected with amyloid fibrils. These results elucidate the potential epigenetic mechanism underlying the upregulated expression of Cdk5 induced by amyloid fibrils and provided novel insights into the pathogenic mechanism of Alzheimer’s disease.
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References
Adwan L, Zawia NH (2013) Epigenetics: a novel therapeutic approach for the treatment of Alzheimer’s disease. Pharmacol Ther 139:41–50. doi:10.1016/j.pharmthera.2013.03.010
Ahmed T, Enam SA, Gilani AH (2010) Curcuminoids enhance memory in an amyloid-infused rat model of Alzheimer’s disease. Neuroscience 169:1296–1306. doi:10.1016/j.neuroscience.2010.05.078
Chacon MA, Barria MI, Soto C, Inestrosa NC (2004) Beta-sheet breaker peptide prevents Abeta-induced spatial memory impairments with partial reduction of amyloid deposits. Mol Psychiatry 9:953–961. doi:10.1038/sj.mp.4001516
Cheung ZH, Ip NY (2012) Cdk5: a multifaceted kinase in neurodegenerative diseases. Trends Cell Biol 22:169–175. doi:10.1016/j.tcb.2011.11.003
Cheung ZH, Fu AK, Ip NY (2006) Synaptic roles of Cdk5: implications in higher cognitive functions and neurodegenerative diseases. Neuron 50:13–18. doi:10.1016/j.neuron.2006.02.024
Colledge M et al (2003) Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 40:595–607
Coppieters N, Dieriks BV, Lill C, Faull RL, Curtis MA, Dragunow M (2014) Global changes in DNA methylation and hydroxymethylation in Alzheimer’s disease human brain. Neurobiol Aging 35:1334–1344. doi:10.1016/j.neurobiolaging.2013.11.031
Cruz JC, Tsai LH (2004) Cdk5 deregulation in the pathogenesis of Alzheimer’s disease. Trends Mol Med 10:452–458. doi:10.1016/j.molmed.2004.07.001
Feng J et al (2010) Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci 13:423–430. doi:10.1038/nn.2514
Flaherty DB, Soria JP, Tomasiewicz HG, Wood JG (2000) Phosphorylation of human tau protein by microtubule-associated kinases: GSK3beta and cdk5 are key participants. J Neurosci Res 62:463–472. doi:10.1002/1097-4547(20001101)62:3<463:AID-JNR16>3.0.CO;2-7
Graff J, Kim D, Dobbin MM, Tsai LH (2011) Epigenetic regulation of gene expression in physiological and pathological brain processes. Physiol Rev 91:603–649. doi:10.1152/physrev.00012.2010
Graff J et al (2012) An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483:222–226. doi:10.1038/nature10849
Guan JS et al (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459:55–60. doi:10.1038/nature07925
Lai KO et al (2012) TrkB phosphorylation by Cdk5 is required for activity-dependent structural plasticity and spatial memory. Nat Neurosci 15:1506–1515. doi:10.1038/nn.3237
Lee KY, Clark AW, Rosales JL, Chapman K, Fung T, Johnston RN (1999) Elevated neuronal Cdc2-like kinase activity in the Alzheimer disease brain. Neurosci Res 34:21–29
Lee J, Yun N, Kim C, Song MY, Park KS, Oh YJ (2014) Acetylation of cyclin-dependent kinase 5 is mediated by GCN5. Biochem Biophys Res Commun 447:121–127. doi:10.1016/j.bbrc.2014.03.118
Lian S et al (2013) Transcriptional activation of mina by sp1/3 factors. PLoS one 8:e80638. doi:10.1371/journal.pone.0080638
Lubin FD, Roth TL, Sweatt JD (2008) Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J Neurosci 28:10576–10586. doi:10.1523/JNEUROSCI.1786-08.2008
Mapelli M, Massimiliano L, Crovace C, Seeliger MA, Tsai LH, Meijer L, Musacchio A (2005) Mechanism of CDK5/p25 binding by CDK inhibitors. J Med Chem 48:671–679. doi:10.1021/jm049323m
Mastroeni D, McKee A, Grover A, Rogers J, Coleman PD (2009) Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer’s disease. PloS one 4:e6617. doi:10.1371/journal.pone.0006617
Pascual M, Do Couto BR, Alfonso-Loeches S, Aguilar MA, Rodriguez-Arias M, Guerri C (2012) Changes in histone acetylation in the prefrontal cortex of ethanol-exposed adolescent rats are associated with ethanol-induced place conditioning. Neuropharmacology 62:2309–2319. doi:10.1016/j.neuropharm.2012.01.011
Pita-Almenar JD, Zou S, Colbert CM, Eskin A (2012) Relationship between increase in astrocytic GLT-1 glutamate transport and late-LTP. Learn Mem 19:615–626. doi:10.1101/lm.023259.111
Provencal N et al (2013) Differential DNA methylation regions in cytokine and transcription factor genomic loci associate with childhood physical aggression. PLoS one 8:e71691. doi:10.1371/journal.pone.0071691
Roselli F, Livrea P, Almeida OF (2011) CDK5 is essential for soluble amyloid beta-induced degradation of GKAP and remodeling of the synaptic actin cytoskeleton. PLoS one 6:e23097. doi:10.1371/journal.pone.0023097
Rudenko A, Tsai LH (2014) Epigenetic modifications in the nervous system and their impact upon cognitive impairments. Neuropharmacology 80:70–82. doi:10.1016/j.neuropharm.2014.01.043
Sabatino L et al (2012) UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression. Oncogene 31:5061–5072. doi:10.1038/onc.2012.3
Shipton OA et al (2011) Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation. J Neurosci 31:1688–1692. doi:10.1523/JNEUROSCI.2610-10.2011
Smith GK, Kesner RP, Korenberg JR (2013) Dentate gyrus mediates cognitive function in the Ts65Dn/DnJ mouse model of down syndrome. Hippocampus. doi:10.1002/hipo.22229
Sobue K, Agarwal-Mawal A, Li W, Sun W, Miura Y, Paudel HK (2000) Interaction of neuronal Cdc2-like protein kinase with microtubule-associated protein tau. J Biol Chem 275:16673–16680. doi:10.1074/jbc.M000784200
Sung YM et al (2013) Mercaptoacetamide-based class II HDAC inhibitor lowers Abeta levels and improves learning and memory in a mouse model of Alzheimer’s disease. Exp Neurol 239:192–201. doi:10.1016/j.expneurol.2012.10.005
Typlt M, Mirkowski M, Azzopardi E, Ruettiger L, Ruth P, Schmid S (2013) Mice with Deficient BK Channel Function Show Impaired Prepulse Inhibition and Spatial Learning, but Normal Working and Spatial Reference Memory. PLoS one 8:e81270. doi:10.1371/journal.pone.0081270
van den Hove DL, Kenis G, Rutten BP (2014) Epigenetic dysregulation in Alzheimer’s disease: cause or consequence? Epigenomics 6:9–11. doi:10.2217/epi.13.84
Zempel H, Thies E, Mandelkow E, Mandelkow EM (2010) Abeta oligomers cause localized Ca(2 +) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30:11938–11950. doi:10.1523/JNEUROSCI.2357-10.2010
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This work was supported by Science and Technology Plan Projects of Hunan Province Science and Technology Department (2011WK3046).
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Li, L., Zhang, C., Zi, X. et al. Epigenetic modulation of Cdk5 contributes to memory deficiency induced by amyloid fibrils. Exp Brain Res 233, 165–173 (2015). https://doi.org/10.1007/s00221-014-4100-0
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DOI: https://doi.org/10.1007/s00221-014-4100-0