Interrelationship between the Levels of C9orf72 and Amyloid-β Protein Precursor and Amyloid-β in Human Cells and Brain Samples

J Alzheimers Dis. 2018;62(1):269-278. doi: 10.3233/JAD-170362.


A subset of C9orf72 repeat expansion-carrying frontotemporal dementia patients display an Alzheimer-like decrease in cerebrospinal fluid amyloid-β (Aβ) biomarker levels. We report that downregulation of C9orf72 in non-neuronal human cells overexpressing amyloid-β protein precursor (AβPP) resulted in increased levels of secreted AβPP fragments and Aβ, while levels of AβPP or its C-terminal fragments (CTFs) remained unchanged. In neuronal cells, AβPP and C83 CTF levels were decreased upon C9orf72 knockdown, but those of secreted AβPP fragments or Aβ remained unchanged. C9orf72 protein levels significantly increased in human brain with advancing neurofibrillary pathology and positively correlated with brain Aβ42 levels. Our data suggest that altered C9orf72 levels may lead to cell-type specific alterations in AβPP processing, but warrant further studies to clarify the underlying mechanisms.

Keywords: Alzheimer’s disease; C9orf72; amyloid-β; amyloid-β protein precursor; frontotemporal dementia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism*
  • Brain / metabolism*
  • Brain / pathology
  • C9orf72 Protein / genetics
  • C9orf72 Protein / metabolism*
  • Cell Line, Tumor
  • Cohort Studies
  • Gene Expression
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • RNA, Messenger / metabolism
  • RNA, Small Interfering


  • Amyloid beta-Peptides
  • C9orf72 Protein
  • C9orf72 protein, human
  • RNA, Messenger
  • RNA, Small Interfering