Evidence for Decreased Nucleolar PARP-1 as an Early Marker of Cognitive Impairment

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.

Altered gut microbiota correlates with cognitive impairment in Chinese children with Down’s syndrome

“…The random forest model of the predominant taxa in the fecal microbiota used to identify DS in our study had similar area under the ROC curve as previous studies [ 22 ]. The KEGG pathway of ribosomal biogenesis is enriched in DS and is closely related to cognitive impairment [ 32 , 33 ], Allen et al reported that transient disruption of ribosome biogenesis could cause memory impairment [ 34 ], whereas persistent severe disruption can lead to cell death due to insufficient protein synthesis [ 35 , 36 ]. Therefore, gut microbiota alterations may also affect cognitive function via the ribosomal biogenesis pathway.…”

Nicotinamide, a Poly [ADP-Ribose] Polymerase 1 (PARP-1) Inhibitor, as an Adjunctive Therapy for the Treatment of Alzheimer’s Disease

“…The KO of TRPM2 suppressed microglial activation in the APP/PS1 transgenic AD mouse model (Ostapchenko et al, 2015) and involvement of astrocytic PARP-1 is also described by Aβ damage (Abeti and Duchen, 2012;Angelova and Abramov, 2014). Furthermore, recent evidence shows a reduced level of PARP-1 nucleolar immunohistochemical staining in hippocampal pyramidal cells in AD and MCI patients (Regier et al, 2019). These findings strongly support a key role for PARP-1 in Parthanatos, mitochondrial function and inflammation occurring in AD.…”

The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases

“…Since PARP1 activation has been detected both upstream and downstream of Aβ, activation of PARP1 is implicated as an early and essential event in the pathogenesis of AD [ 208 ]. Furthermore, PARP1 reduction in the nucleus, leading to activation of DNA cytosine-5-methyltransferase 1 and silencing of nucleolar rRNA gene (rDNA), was implicated as an early marker of cognitive impairment in AD [ 209 ]. These studies therefore provide evidence that dysregulation of PARP1 is a consistent feature of AD, thus implicating parthanatos in neuronal death in this condition.…”