Abstract
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.
Highlights
Intracellular accumulation of neurofibrillary tau tangles is the common hallmark of Alzheimer's disease (AD; Dubois et al, 2014)
We discovered that euchromatic histone- lysine N-methyltransferase 2 (EHMT2) was significantly elevated in prefrontal cortex (PFC) of P301S Tau mice, and inhibition of euchromatichistone-lysine N-methyltransferase (EHMT) led to the amelioration of behavioral and synaptic deficits, as well as the normalization of large-scale gene expression
Our current study has provided evidence demonstrating that EHMT2 (G9a), which catalyzes the repressive histone mark H3K9me2 (Barski et al, 2007) at learning and memory genes (Kramer et al, 2011), is highly elevated in PFC neurons of P301S Tau transgenic mice
Summary
Intracellular accumulation of neurofibrillary tau tangles is the common hallmark of Alzheimer's disease (AD; Dubois et al, 2014). Controlling gene expression through epigenetic regulation, including chromatin remodeling and histone modification, provides a potential avenue to restore synaptic and cognitive plasticity in AD (Li et al, 2019; Yuan et al, 2020). We discovered that euchromatic histone- lysine N-methyltransferase 2 (EHMT2) was significantly elevated in PFC of P301S Tau mice, and inhibition of EHMT led to the amelioration of behavioral and synaptic deficits, as well as the normalization of large-scale gene expression. It supports the potential of EHMT as a target for the treatment of tauopathies, including AD
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