By Rachel Hull, Biochemistry & Molecular Biology, ’19
Author’s note: I first learned about this news through an article on Big Think that provided few details about the science behind the breakthrough. Reading the original research paper clarified both how this research had been conducted and what was so noteworthy about it. Given the prevalence of Alzheimer’s disease, this new study may yet prove to be instrumental in the disorder’s treatment.
A new study by Zheng et al. has elucidated a novel way of potentially treating Alzheimer’s disease (1). This neurodegenerative disorder affects a large portion of the elderly population, presenting as a functional decline in cognition and behavior often associated with dementia (1, 2). As such, much attention has been paid toward finding its underlying causes and its amenability to possible treatments (1).
There are currently only two anti-Alzheimer’s disease medications approved by the Federal Drug Administration, but much work is being done to illuminate possible alternatives (1, 2). Zheng et al.’s approach involves epigenetic dysregulation, a means through which gene expression in the brain can be altered. Using a late-stage familiar Alzheimer’s disease (FAD) mouse model, Zheng et al. found that levels of histone methylation were significantly increased in the prefrontal cortex (PFC), a key region involved in the disease. These same findings were observed in the PFC of post-mortem tissues from patients with Alzheimer’s disease. In particular, histone H3 dimethylation at lysine 9 (H3K9me2) was elevated in the PFC region for both of these models (1).
Zheng et al. focused on the euchromatic histone methyltransferases EHMT1 and EHMT2, which specifically catalyze H3K9 dimethylation, as the culprits for the observed phenomenon. They discovered that the levels of these enzymes were unusually high in the PFC of aged FAD mice (1).
These abnormal histone modifications were linked to a reduction in the transcription and expression of glutamate receptors — especially AMPA and NMDA receptors — in the PFC of aged FAD mice. Upon treating FAD mice with BIX01294, a specific EHMT1/2 inhibitor, Zheng et al. found that the H3K9me2 level was reduced. Additionally, the transcription and expression of glutamate receptors was restored in the PFC (1).
The loss of glutamate receptor transcription and expression in aged FAD mice also resulted in reduced glutamatergic signaling in the PFC of FAD mice. When treated with selective EHMT1/2 inhibitors, synaptic responses mediated by AMPA and NMDA receptors were brought back to normal levels. Knockdown of EHMT1 and EHMT2 in FAD mice produced the same effect. Notably, Zheng et al. also observed this recovery of synaptic function in the hippocampus, which showed the same alterations in H3K9me2 and glutamate receptors as the PFC (1).
Genome-wide analysis revealed that in FAD mice, genes involved in neuronal signaling — including glutamate receptors — showed enriched H3K9 dimethylation. This enrichment could be largely reversed by treatment with the aforementioned inhibitor BIX 01294 (1).
Zheng et al. also performed behavioral tests with FAD mice to gauge the potential of EHMT1/2 inhibitors as therapeutic agents. The tests were designed to assess the mice’s novel object recognition memory, working memory, and spatial memory. After treatment with these inhibitors, the mice showed marked improvements in all three categories (1).
Though the etiology of Alzheimer’s disease remains uncertain, research continues on novel ways to treat it. Zheng et al.’s recent study suggests that epigenetic modifications such as histone methylation may play a key role in the disorder’s progression. In time, this epigenetic approach could be applied toward drug therapy for Alzheimer’s disease, representing a promising avenue for future research into the matter.
- Zheng Y, Liu A, Wang Z-J, Cao Q, Wang W, Lin L, Ma K, Zhang F, Wei J, Matas E, et al. Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer’s disease. Brain. 2019 Jan 22. doi:10.1093/brain/awy354.
- Atri A. The Alzheimer’s disease clinical spectrum: diagnosis and management. Medical Clinics of North America. 2019;103(2):263–293. doi:10.1016/j.mcna.2018.10.009.