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. 2017 Apr 13;26(4):693-702.
doi: 10.3727/096368916X694184. Epub 2016 Nov 30.

Regulator of Cell Cycle (RGCC) Expression During the Progression of Alzheimer's Disease

Scott E Counts, Elliott J Mufson

Regulator of Cell Cycle (RGCC) Expression During the Progression of Alzheimer's Disease

Scott E Counts et al. Cell Transplant. .

Abstract

Unscheduled cell cycle reentry of postmitotic neurons has been described in cases of mild cognitive impairment (MCI) and Alzheimer's disease (AD) and may form a basis for selective neuronal vulnerability during disease progression. In this regard, the multifunctional protein regulator of cell cycle (RGCC) has been implicated in driving G1/S and G2/M phase transitions through its interactions with cdc/cyclin-dependent kinase 1 (cdk1) and is induced by p53, which mediates apoptosis in neurons. We tested whether RGCC levels were dysregulated in frontal cortex samples obtained postmortem from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), MCI, or AD. RGCC mRNA and protein levels were upregulated by ∼50%-60% in MCI and AD compared to NCI, and RGCC protein levels were associated with poorer antemortem global cognitive performance in the subjects examined. To test whether RGCC might regulate neuronal cell cycle reentry and apoptosis, we differentiated neuronotypic PC12 cultures with nerve growth factor (NGF) followed by NGF withdrawal to induce abortive cell cycle activation and cell death. Experimental reduction of RGCC levels increased cell survival and reduced levels of the cdk1 target cyclin B1. RGCC may be a candidate cell cycle target for neuroprotection during the onset of AD.

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Figures

Figure 1.
Figure 1.
p53 (tp53) and protein regulator of cell cycle (rgcc) gene expression levels are increased in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Box plots show relative expression levels of (A) tp53, (B) rgcc, and (C) cdc/cyclin-dependent kinase 1 (cdk1) normalized to glyceraldehyde 3-phosphate dehydrogenase (gapdh) levels (mean ± max/min; arbitrary units) in total RNA derived from no cognitive impairment (NCI), MCI, and AD cases. *p < 0.05 versus NCI, via one-way analysis of variance (ANOVA) with Bonferroni post hoc comparisons.
Figure 2.
Figure 2.
Regulator of cell cycle (rgcc) protein levels are increased in mild cognitive impairment (MCI) and Alzheimer's disease (AD). (A) Representative Western blot shows greater RCGG immunoreactivity (~15 kDa) in tissue extracts derived from MCI and AD cases compared to no cognitive impairment (NCI) cases; levels of β-actin were equivalent across samples. (B) Box plots show relative quantitative measurements of RGCC immunoreactivity normalized to β-actin signals (mean+max/min; arbitrary units) in the three diagnostic groups. *p < 0.05 versus NCI, via one-way analysis of variance (ANOVA) with Bonferroni post hoc comparisons.
Figure 3.
Figure 3.
Regulator of cell cycle (rgcc) inhibition rescues PC12 cells from cell death induced by nerve growth factor (NGF) withdrawal. (A) Bar graph shows relative levels of cell survival as measured by the LIVE/DEAD assay [mean ± standard deviation (SD); arbitrary units] for PC12 cultures maintained on NGF, deprived of NGF for 48 h, deprived of NGF for 48 h in the presence of rgcc siRNA, or deprived of NGF for 48 h in the presence of scrambled control siRNA. (B) Bar graph shows relative levels of cyclin b1 (ccnb1) transcript levels as measured by quantitative polymerase chain reaction (qPCR) (mean ± SD; arbitrary units) for PC12 cultures maintained on NGF, deprived of NGF for 48 h, deprived of NGF for 48 h in the presence of rgcc siRNA, or deprived of NGF for 48 h in the presence of scrambled control siRNA. *p < 0.05; *p < 0.01 versus NGF, via one-way analysis of variance (ANOVA) with Bonferroni post hoc comparisons.
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