Abstract
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein that regulates gene expression through poly(ADP)-ribosylation, resulting in the loosening of chromatin structure. PARP-1 enzymatic activity has been shown to be necessary for the expression of several genes required for memory formation and consolidation. Previously, we showed that nucleolar PARP-1 is significantly decreased in hippocampal pyramidal cells in Alzheimer's disease (AD). We proposed that the displacement of PARP-1 from the nucleolus results in downregulation of new rRNA expression and ribosome biogenesis, leading to cognitive impairment. To further investigate the relationship between nucleolar PARP-1 and memory impairment, we examined PARP-1 expression in the hippocampi of individuals with mild cognitive impairment (MCI) compared to control and AD cases. We used immunohistochemical techniques to examine the nucleolar distribution of PARP-1 in the Cornu Ammonis (CA region) of the hippocampus. PARP-1 positive cells were then scored for the presence or absence of PARP-1 in the nucleolus. We found a significant decrease of PARP-1 staining in the nucleolar compartment of hippocampal pyramidal cells in MCI compared with Control and AD. When the four CA (CA1-4) regions were considered separately, only the CA1 region showed significant differences in nucleolar PARP-1 with Control > AD > MCI cases. Categorization of nucleolar PARP-1 into “distinct” and “diffuse” groups suggest that most of the changes occur within the distinct group. In addition, measurements of the nucleolar diameter of nucleolar PARP-1 positive cells in CA2 and CA4 showed Control > MCI. Thus, MCI cases had a lower percentage of PARP-1 nucleolar positive cells in CA1 and smaller nucleolar diameters in CA2 and CA4, compared to Control. Our data suggest that disruption of nucleolar form and function is an early and important step in the progression of cognitive impairment.
Highlights
Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that is characterized clinically by memory loss and cognitive impairment, and neuropathologically by extracellular aggregations of β-amyloid (Aβ) protein and intracellular aggregations of hyper-phosphorylated tau protein [1, 2]
To characterize the percentage of nucleoli that are positive for PARP-1 across the Cornu Ammonis (CA) regions of the hippocampus (CA1-CA4), sections were stained with PARP-1 antibody and categorized as present or absent for PARP-1
We found a reduction in the percentage of pyramidal cells with PARP-1 staining in the nucleoli of MCI cases compared to Control and AD cases across the CA (Figure 1(b); Analysis of Variance (ANOVA): F2,52 = 7.819 p
Summary
Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that is characterized clinically by memory loss and cognitive impairment, and neuropathologically by extracellular aggregations of β-amyloid (Aβ) protein (neuritic plaques) and intracellular aggregations of hyper-phosphorylated tau protein (neurofibrillary tangles) [1, 2]. Plaques and tangles are necessary for a neuropathologic diagnosis, the extent of these pathologies does not correlate well with cognitive decline early in disease progression [4]. It is generally believed that many of the drugs tested in clinical trials fail because the therapy was started too late with respect to the progression of the disease [7,8,9]. There is interest in identifying early (pre-clinical) markers of AD in order to re-test therapies that failed in later stages of the disease [3, 9]. This study was designed to explore the possibility of PARP-1 being one of those markers
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