Epigenetic abnormality is implicated in
neurodegenerative diseases associated with cognitive deficits, such as
Alzheimer's disease (AD). A common feature of AD is the accumulation of neurofibrillary tangles composed of hyperphosphorylated tau. Transgenic mice expressing mutant P301S human
tau protein develop AD-like progressive tau pathology and
cognitive impairment. Here, we show that the euchromatic
histone-lysine N-methyltransferase 2 (EHMT2) is significantly elevated in the prefrontal cortex (PFC) of P301S Tau mice (5-7 months old), leading to the increased repressive histone mark, H3K9me2, which is reversed by treatment with the selective EHMT inhibitor
UNC0642. Behavioral assays show that
UNC0642 treatment induces the robust rescue of spatial and recognition
memory deficits in P301S Tau mice. Concomitantly, the diminished PFC neuronal excitability and glutamatergic synaptic transmission in P301S Tau mice are also normalized by
UNC0642 treatment. In addition, EHMT inhibition dramatically attenuates the hyperphosphorylated tau level in PFC of P301S Tau mice. Transcriptomic analysis reveals that
UNC0642 treatment of P301S Tau mice has normalized a number of dysregulated genes in PFC, which are enriched in cytoskeleton and extracellular matrix organization,
ion channels and transporters, receptor signaling, and stress responses. Together, these data suggest that targeting
histone methylation
enzymes to adjust gene expression could be used to treat cognitive and synaptic deficits in
neurodegenerative diseases linked to
tauopathies.