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Alzheimer disease is a chronic, progressive, and irreversible neurodegenerative disorder and the most common cause of dementia in older adults. It leads to gradual neuronal loss, causing cognitive decline, behavioral changes, and loss of functional independence.Risk Factors and EtiologyThe disease is multifactorial. Age is the strongest risk factor, with prevalence doubling every 5 years after age 65. Genetic factors include mutations in genes such as APP, PSEN1, and PSEN2, which are associated...
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Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease

Leonidas Chouliaras1, Diego Mastroeni, Elaine Delvaux

  • 1School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, European Graduate School of Neuroscience (EURON), Maastricht University Medical Centre, Maastricht, the Netherlands.

Neurobiology of Aging
|April 16, 2013
PubMed
Summary

Alzheimer's disease (AD) is linked to significant decreases in DNA methylation (5-mC) and hydroxymethylation (5-hmC) markers in the brain. These epigenetic changes correlate with increased amyloid plaque pathology in AD patients.

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Area of Science:

  • Neuroscience
  • Epigenetics
  • Pathology

Background:

  • Epigenetic dysregulation, specifically DNA methylation and hydroxymethylation, is implicated in Alzheimer's disease (AD) pathophysiology.
  • Understanding the cell-type specificity and link to AD pathology of these epigenetic markers is crucial.

Purpose of the Study:

  • To quantify levels of 5-methylcytidine (5-mC) and 5-hydroxymethylcytidine (5-hmC) in the hippocampus of AD patients versus controls.
  • To investigate cell-type specificity and correlate epigenetic markers with AD pathology (amyloid plaques, neurofibrillary tangles).

Main Methods:

  • Quantitative immunohistochemistry was used to measure 5-mC and 5-hmC levels in hippocampal tissue from 10 AD patients and 10 age-matched controls.
  • Analysis included cell-type and hippocampal subregion specificity, assessment in monozygotic twins discordant for AD, and correlation with neuropathology.

Main Results:

  • AD patients exhibited significant reductions in hippocampal 5-mC (19.6%) and 5-hmC (20.2%) compared to controls.
  • Similar decreases were observed in an AD-discordant monozygotic twin pair.
  • Both 5-mC and 5-hmC levels negatively correlated with hippocampal amyloid plaque load.

Conclusions:

  • Alzheimer's disease is associated with substantial alterations in DNA methylation and hydroxymethylation in the hippocampus.
  • These findings support a role for epigenetic modifications in AD pathogenesis and suggest potential therapeutic targets.