title: Epigenetic modulation of Cdk5 contributes to memory deficiency induced by amyloid fibrils.
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.
authors.affiliation: Department of Neurology, The Third Xiangya Hospital of Central South University, 138 Tongzipo Rd, Changsha, 410013, Hunan, China.
authors.forename: Liuhong
authors.initials: L
authors.lastname: Li
authors.forename: Chunqiang
authors.initials: C
authors.lastname: Zhang
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zi
authors.forename: Qiuyun
authors.initials: Q
authors.lastname: Tu
authors.forename: Ke
authors.initials: K
authors.lastname: Guo
mesh_terms: D000682:Amyloid / Q000494:pharmacology*; D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology*
chemical_list: D000682:Amyloid; D051360:Cyclin-Dependent Kinase 5