The dysregulation of the G1/S transition point in Alzheimer's disease

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Abstract

Background: The cell cycle hypothesis for the pathogenesis of Alzheimer's disease postulates that the development of the disease-specific pathology and associated cell death is the results of neuronal cell cycle re-entry and subse quent regulatory failure at the Gl/S transition point. Many identified risk fac-tors of AD, such as elevated plasma homocysteine levels ageing menopause low level prolonged oxidative stress, can potentially represent the mitogenic stimulus necessary to trigger the cell cycle in neurons. However, while cell cycle re-entry of neurons appears to be a prerequisite of Alzheimer's disease, on its own is not sufficient to cause the disease. The difference between the healthy aging and AD is the extent of cell cycle progression following cell cycle re-entry. Thus the transition from healthy ageing to AD is the point when neurons bypass the G1/S restriction point. There is increasing evidence suggesting that this cell cycle regulatory failure in AD is not restricted to neu rons. Methods: Peripheral blood lymphocytes from AD patient (probable AD), control subjects and patients who fulfill the criteria for mild cognitive impairment (MCI) were cultured with PHA and treated with rapamycin. The effect of rapamycin on the Gl/S transition was quantified using flow cytom etry. Results: We have found that the response to rapamycin was a signifi cantly stronger in control subjects than in AD patients. The rapamycin response discriminates between the two groups with 80% sensitivity and 80% specificity. We have also found that 40% of the MCI patients show a reg ulatory deficit similar to AD patients. Conclusions: Our study indicates that the detection of the G1/S regulatory failure from peripheral lymphocytes may represent an early biomarker of Alzheimer's disease. We believe that our novel biomarker would allow the early identification of MCI patients who will develop dementia later.
Original languageEnglish
Title of host publicationAlzheimer's and Dementia
Place of PublicationZ. Nagy, University of Birmingham, Birmingham, United Kingdom. E-mail: z.nagy@bham.ac.uk
PublisherElsevier
Pages171
Number of pages1
ISBN (Print)1552-5260
Publication statusPublished - 2009

Publication series

NameAlzheimer's and Dementia
Volume5

Keywords

  • *Alzheimer disease
  • aging
  • biological marker
  • cell cycle
  • cell cycle progression
  • cell death
  • dementia
  • homocysteine
  • hypothesis
  • menopause
  • mild cognitive impairment
  • nerve cell
  • oxidative stress
  • pathogenesis
  • pathology
  • patient
  • peripheral lymphocyte
  • phytohemagglutinin
  • plasma
  • rapamycin
  • risk
  • stimulus

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