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

Michael P. Walker, Frank M. Laferla, Salvatore Oddo, Gregory J. Brewer

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

With aging and Alzheimer's disease (AD), there is an increased sensitivity to stress along with declines in the memory-associated neurotrophin brain-derived 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 non-transgenic 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.

Original languageEnglish (US)
Pages (from-to)519-531
Number of pages13
JournalAge
Volume35
Issue number3
DOIs
StatePublished - Jun 2013
Externally publishedYes

Fingerprint

Histone Code
Epigenomics
Alzheimer Disease
Neurons
Acetylation
Methylation
Histones
Histone Deacetylases
Brain-Derived Neurotrophic Factor
Memory Disorders
Nerve Growth Factors

Keywords

  • 3xTg-AD
  • Epigenetics
  • Histone acetylation
  • Histone methylation

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

Cite this

Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer's disease. / Walker, Michael P.; Laferla, Frank M.; Oddo, Salvatore; Brewer, Gregory J.

In: Age, Vol. 35, No. 3, 06.2013, p. 519-531.

Research output: Contribution to journalArticle

Walker, Michael P. ; Laferla, Frank M. ; Oddo, Salvatore ; Brewer, Gregory J. / Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer's disease. In: Age. 2013 ; Vol. 35, No. 3. pp. 519-531.
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