RGD Reference Report - Cell cycle checkpoint abnormalities during dementia: A plausible association with the loss of protection against oxidative stress in Alzheimer's disease . - Rat Genome Database

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Cell cycle checkpoint abnormalities during dementia: A plausible association with the loss of protection against oxidative stress in Alzheimer's disease .

Authors: Katsel, P  Tan, W  Fam, P  Purohit, DP  Haroutunian, V 
Citation: Katsel P, etal., PLoS One. 2013 Jul 5;8(7):e68361. doi: 10.1371/journal.pone.0068361. Print 2013.
RGD ID: 10047419
Pubmed: PMID:23861893   (View Abstract at PubMed)
PMCID: PMC3702571   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0068361   (Journal Full-text)

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. METHODS AND FINDINGS: 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease disease_progressionIEP 10047419; 10047419 RGD 
Alzheimer's disease  IEP 10047419 RGD 
Alzheimer's disease disease_progressionISOATM (Homo sapiens)10047419; 10047419 RGD 
Alzheimer's disease  ISOATR (Homo sapiens)10047419; 10047419 RGD 
Alzheimer's disease disease_progressionISOMDM4 (Homo sapiens)10047419; 10047419 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Atm  (ATM serine/threonine kinase)
Atr  (ATR serine/threonine kinase)
Mdm4  (MDM4 regulator of p53)

Genes (Mus musculus)
Atm  (ataxia telangiectasia mutated)
Atr  (ataxia telangiectasia and Rad3 related)
Mdm4  (transformed mouse 3T3 cell double minute 4)

Genes (Homo sapiens)
ATM  (ATM serine/threonine kinase)
ATR  (ATR serine/threonine kinase)
MDM4  (MDM4 regulator of p53)


Additional Information