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.

The Role of Cdk5 in Alzheimer’s Disease

“…Numerous studies have presented compelling evidence implicating Cdk5 in homeostatic synaptic formation and plasticity [76] (Fig. 2).…”

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…These deficits were caused by an inability of TrkB receptors to be phosphorylated and interact with Rac1 for dendritic spine remodeling and reveals the importance of Cdk5 for LTP and spatial memory formation (86). Interestingly, abnormal Cdk5 activity has been implicated in AD pathology (100)(101)(102)(103).…”

Epigenetic Changes in Aging and Age-related Disease

“…For example, one study found that glioblastoma cells which express 2.6-fold higher levels of APP display a global reduction DNA methylation and this hypomethylation resulted in the ectopic expression of several ADassociated genes such as PS1, BACE1 and APP itself [107]. In the rat model of AD, increased H3 acetylation and decreased promoter methylation in the region of cyclin dependant kinase 5 (cdk5), lead to increased hippocampal cdk5 activity, tau phosphorylation, synaptic dysfunction and memory loss [104].…”

“…AD is a progressive neurodegenerative disorder that can occur in old age and is often characterized by accumulation of amyloid β peptides and abnormally phosphorylated tau proteins [104,105]. The altered methylation state of the AD brain typically results in gene expression alterations in two primary pathogenic pathways: amyloid precursor protein (APP) processing and tau hyper phosphorylation [102,106].…”