Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer's disease.
Qing CaoWei WangJamal B WilliamsFengwei YangZi-Jun WangZhen YanPublished in: Science advances (2020)
Epigenetic aberration is implicated in aging and neurodegeneration. Using postmortem tissues from patients with Alzheimer's disease (AD) and AD mouse models, we have found that the permissive histone mark H3K4me3 and its catalyzing enzymes are significantly elevated in the prefrontal cortex (PFC). Inhibiting H3K4-specific methyltransferases with the compound WDR5-0103 leads to the substantial recovery of PFC synaptic function and memory-related behaviors in AD mice. Among the up-regulated genes reversed by WDR5-0103 treatment in PFC of AD mice, many have the increased H3K4me3 enrichment at their promoters. One of the identified top-ranking target genes, Sgk1, which encodes serum and glucocorticoid-regulated kinase 1, is also significantly elevated in PFC of patients with AD. Administration of a specific Sgk1 inhibitor reduces hyperphosphorylated tau protein, restores PFC glutamatergic synaptic function, and ameliorates memory deficits in AD mice. These results have found a novel epigenetic mechanism and a potential therapeutic strategy for AD and related neurodegenerative disorders.
Keyphrases
- prefrontal cortex
- dna methylation
- mouse model
- gene expression
- genome wide
- traumatic brain injury
- high fat diet induced
- working memory
- transcription factor
- type diabetes
- metabolic syndrome
- drug delivery
- cancer therapy
- small molecule
- combination therapy
- insulin resistance
- protein protein
- skeletal muscle
- tyrosine kinase
- drug induced
- binding protein
- replacement therapy