Suppression of KDM5C mitigates the symptoms of Alzheimer's disease by up-regulating BDNF expression

Histone methylation, a common form of chromatin remodeling, has been found to be associated with various neurological and cognitive disorders. However, little is known about how this mechanism contributes to the onset and progression of Alzheimer's disease (AD). Here, we found that lysine demethylase 5C (KDM5C), a histone H3 lysine 4 di- and tri-methyl (H3K4me2/3)-specific demethylase encoded by an X-linked mental retardation-related gene, displayed a progressive increase in the hippocampus with age in 3 × Tg-AD mice. Suppression of KDM5C partially mitigated the cognitive decline according to water maze, Y maze, and novel object recognition tests. In addition, significantly decreased amyloid plaques, enhanced long-term potentiation (LTP), and up-regulated expression of synaptic proteins were observed in KDM5C knockdown 3 × Tg-AD mice. Mechanistically, suppression of KDM5C could promote the expression of brain-derived neurotrophic factor (BDNF) to partially protect hippocampal neurons from beta-amyloid damage. In the promoter region of Bdnf, KDM5C was bound to the repressor element-1 (RE-1) motif to reduce the nearby H3K4me3 level and inhibit gene transcription. Mutations in the RE-1 motif reversed the inhibitory effect of KDM5C. Our results emphasize that KDM5C excess is one of the reasons for the onset and progression of AD and that suppression of KDM5C in the hippocampus should be considered a potential therapeutic target to ameliorate cognitive impairment and pathological symptoms in AD.