Abstract
BackgroundIncreasing 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 FindingsIn 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.ConclusionsThese 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.
Highlights
Alzheimer’s disease (AD) is the leading cause of dementia in the elderly and is associated with progressive memory loss, cognitive impairment and neurodegeneration
These results support the activation of an Ataxia-telangiectasia mutated (ATM) signaling and DNA damage response network during the progression of AD dementia, while the progressive decrease in the levels of tumor protein p53 (TP53)-induced glycolysis and apoptosis regulator (TIGAR) suggests loss of protection initiated by ATM-p53 signaling against intensifying oxidative stress in AD
This analysis results in sets of differentially expressed genes with corresponding individual tscore values, which were uploaded to the MetaCore database and software suite (Thomson Reuter) and subjected to the multiple experiments comparison analysis according to the MetaCore guidelines
Summary
Alzheimer’s disease (AD) is the leading cause of dementia in the elderly and is associated with progressive memory loss, cognitive impairment and neurodegeneration. Observations in AD of phenotypes such as tetraploidy [11], binuclear neuronal cells [25] and premature centromere separation that are rarely present in the brains of unaffected elderly persons, provided additional support for ongoing DNA replication [26,27] and raise the possibility of chromosomal instability in neural cells of AD patients These CCL events appear during early stages of disease [10,27]. 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
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