TIGAR is abundant in large pyramidal neurons in deep cortical layers (V–VI) of STG from the human brain.

<p>(A–C) Immunostaining for TIGAR visualized by peroxidase substrate DAB (brown staining) and counterstained with hematoxylin to visualize nuclei (blue). (D) Single staining with TIGAR; insert -negative control (secondary antibody staining). Strong staining of TIGAR was prevalent in cytoplasm and sometimes shows nuclear or perinuclear localization in large neurons as indicated by arrows (D).</p

Cycle Checkpoint Abnormalities during Dementia: A Plausible Association with the Loss of Protection against Oxidative Stress in Alzheimer’s Disease

<div><p>Background</p><p>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.</p><p>Methods and Findings</p><p>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.</p><p>Conclusions</p><p>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.</p></div

The mitotic cell cycle checkpoint gene network generated by the MetaCore and overlaid with the color coded gene expression changes during dementia.

<p>(red – upregulation; blue – downregulation; combination red/blue – differential effect at various stages of dementia). Highlighted is ATM/ATR regulation of G1/S transition pathways. The tumor protein p53 is a hub gene in this network.</p

Most relevant common and unique gene networks in the STG (BA22) derived from MetaCore analysis by comparing groups of cognitively impaired individuals with cognitively intact controls (CDR = 0).

<p>a Size = number of selected nodes (genes);</p><p>b Pathways = number of MetaCore pathways recognized within network and.</p><p>c G-score = ranks gene networks and based on the enrichment of expressed genes within the network, which is additionally modified with the saturation of the canonical pathways.</p><p>Cell cycle related networks highlighted in bold font.</p

Gene expression changes for ATM/ATR signaling pathway in STG (BA22) during progression of dementia (as a function of CDR).

<p>MDM4, ATM and ATR gene expression levels were significantly different in questionable-mild (CDR 0.5-1, light gray bars) and severe (CDR 2-5, dark gray bars) dementia groups relative to control group (black bars). REVs- relative expression values; * -p<0.05; ** -p≤0.01.</p

Western blot (A) and protein expression levels of TIGAR (B) in STG (BA22) in dementia (CDRs >0.5) and schizophrenia.

<p>TIGAR expression values were normalized to GAPDH. **-p≤0.01; ***-p≤0.001.</p