title: Cell cycle checkpoint abnormalities during dementia: A plausible association with the loss of protection against oxidative stress in Alzheimer's disease [corrected].
abstract: BACKGROUND
  Increasing evidence suggests an association between neuronal cell cycle (CCL) events and the processes that underlie neurodegeneration in Alzheimer's disease (AD). Elevated levels of oxidative stress markers and mitochondrial dysfunction are also among early events in AD. Recent studies have reported the role of CCL checkpoint proteins and tumor suppressors, such as ATM and p53 in the control of glycolysis and oxidative metabolism in cancer, but their involvement in AD remains uncertain.
  
  
  RESULTS
  In this postmortem study, we measured gene expression levels of eight CCL checkpoint proteins in the superior temporal cortex (STC) of persons with varying severities of AD dementia and compare them to those of cognitively normal controls. To assess whether the CCL changes associated with cognitive impairment in AD are specific to dementia, gene expression of the same proteins was also measured in STC of persons with schizophrenia (SZ), which is also characterized by mitochondrial dysfunction. The expression of CCL-checkpoint and DNA damage response genes: MDM4, ATM and ATR was strongly upregulated and associated with progression of dementia (cognitive dementia rating, CDR), appearing as early as questionable or mild dementia (CDRs 0.5-1). In addition to gene expression changes, the downstream target of ATM-p53 signaling - TIGAR, a p53-inducible protein, the activation of which can regulate energy metabolism and protect against oxidative stress was progressively decreased as severity of dementia evolved, but it was unaffected in subjects with SZ. In contrast to AD, different CCL checkpoint proteins, which include p53, CHEK1 and BRCA1 were significantly downregulated in SZ.
  
  
  CONCLUSIONS
  These results support the activation of an ATM signaling and DNA damage response network during the progression of AD dementia, while the progressive decrease in the levels of TIGAR suggests loss of protection initiated by ATM-p53 signaling against intensifying oxidative stress in AD.
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, New York, New York, USA. pavel.katsel@mssm.edu
authors.forename: Pavel
authors.initials: P
authors.lastname: Katsel
authors.forename: Weilun
authors.initials: W
authors.lastname: Tan
authors.forename: Peter
authors.initials: P
authors.lastname: Fam
authors.forename: Dushyant P
authors.initials: DP
authors.lastname: Purohit
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D001344:Autopsy; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D003704:Dementia / Q000235:genetics* / Q000378:metabolism*; D018450:Disease Progression; D053263:Gene Regulatory Networks; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human