Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer’s disease

Abstract

With aging and Alzheimer's disease (AD), there is an increased sensitivity to stress along with declines in the memory-associated neurotrophin brainderived neurotrophic factor in AD. We have replicated this aging phenotype in cultured neurons from aged mice despite being grown in the same environmental conditions as young neurons. This led us to hypothesize that age-related differences in epigenetic acetylation and methylation of histones are associated with age-related gene regulation. We cultured hippocampal/ cortical neurons from the 3xTg-AD mouse model and from non-transgenic mice to quantify single cell acetylation and methylation levels across the life span. In non-transgenic neurons, H3 acetylation was unchanged with age, while H4 acetylation decreased with age of the donor. Compared to nontransgenic neurons, 3xTg-AD neurons had higher levels of H3 and H4 acetylation beginning at 4 months of age. In contrast to non-transgenic neurons, 3xTg-AD neurons increased acetylation with age; 3xTg-AD neurons also responded differently to inhibition of histone deacetylases at an early age. Importantly, treatment of non-transgenic neurons with the AD peptide Aβ also elevated levels of acetylation. We also examined the repressive function of histone H3 lysine 9 (H3K9) methylation. H3K9 methylation increased with age in non-transgenic neurons, which was amplified further in 3xTg-AD neurons. The dominant effect of higher H3K9 methylation was supported by lower Bdnf gene expression in non-transgenic and 3xTg-AD mice. These data show that the epigenetic states of non-transgenic and 3xTg-AD brain neurons are profoundly different and reversible, beginning at 4 months of age when the first memory deficits are reported.

The world of protein acetylation

“…Hypoacetylation of neuroplasticity genes lead to transcriptional downregulation of genes essential for synaptic maintenance, function and neurotransmission. Studies from aging mice and rat brains have shown a reduced acetylation level of H3K9 and H4K12 as well as increased HDAC2 expression, the latter resulting in a hypoacetylated BDNF promoter-region [285][286][287]. In fact, a perturbed HDAC2-BDNF feedback loop has been suggested as a common feature of aging and neurodegeneration.…”

EHMT1/GLP; Biochemical Function and Association with Brain Disorders

“…H3K9 methylation is found to increase with age, and is linked to cognitive decline. Perhaps as a further link with pathological aging, H3K9 methylation was increased in the brains of 3xTg-AD mouse model of Alzheimer's disease [55].…”

Alzheimer's Disease

“…In a study on both aging and AD, global decrease of 5-mC was observed during the aging process, while increase of 5-hmC was observed in 3xTgAD mouse compared to wild-type control (Cadena-del-Castillo et al, 2014). In a study on histone modification, the level of H3/H4 acetylation started to increase at 4 months of age in 3xTgAD mouse, which is a distinctive feature compared to wild-type mice (Walker, LaFerla, Oddo, & Brewer, 2013). In a microRNA study, the upregulation of microRNA in 3xTgAD mouse converged to the regulation of synaptic function, and miR-325 was identified as a key player in both AD pathology development and response to environmental enrichment (Barak et al, 2015).…”