DNA damage-associated oligodendrocyte degeneration precedes amyloid pathology and contributes to Alzheimer's disease and dementia

Kai Hei Tse, Aifang Cheng, Fulin Ma, Karl Herrup

Research output: Journal article publicationJournal articleAcademic researchpeer-review

13 Citations (Scopus)

Abstract

Introduction: In looking for novel non-amyloid-based etiologies for Alzheimer's disease, we explore the hypothesis that age-related myelin loss is an attractive explanation for age-associated cognitive decline and dementia. Methods: We performed a meta-analysis of data in the National Alzheimer's Coordinating Center database accompanied by quantitative histopathology of myelin and oligodendrocytes (OLs) in frontal cortices of 24 clinically characterized individuals. Pathological findings were further validated in an Alzheimer's disease mouse model and in culture. Results: Myelin lesions increased with cognitive impairment in an amyloid-independent fashion with signs of degeneration appearing before neuronal loss. Myelinating OLs in the gray matter showed greater vulnerability than those in white matter, and the degenerative changes correlated with evidence of DNA damage. Similar results were found in myelinating OL cultures where DNA damage caused aberrant OL cell cycle re-entry and death. Discussion: We present the first comprehensive analysis of the cell biology of early myelin loss in sporadic Alzheimer's disease.

Original languageEnglish
Pages (from-to)664-679
Number of pages16
JournalAlzheimer's and Dementia
Volume14
Issue number5
Early online date9 Jan 2018
DOIs
Publication statusPublished - May 2018
Externally publishedYes

Keywords

  • Amyloid plaques
  • Dementia
  • DNA damage
  • Myelin
  • Oligodendrocyte

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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