Epigenetic regulation of adult neural stem cells: implications for Alzheimer’s disease

Fitzsimons, Carlos P.; Bodegraven, Emma J. van; Schouten, Marijn; Lardenoije, Roy; Kompotis, Konstantinos; Kenis, Günter; Hurk, Mark van den; Boks, Marco P.; Biojone, Caroline; Joca, Sâmia Regiane Lourenço; Steinbusch, Harry W.M.; Lunnon, Katie; Mastroeni, Diego; Mill, Jonathan; Lucassen, Paul J.; Coleman, Paul D.; Hove, Daniël L.A. van den; Rutten, Bart P. F.

doi:10.1186/1750-1326-9-25

Cited by 54 publications

(43 citation statements)

References 210 publications

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“…Genes in poised expression states in relevant cell types can be activated by changes in the epigenome later in development or by environmental cues (Creyghton et al., 2010; Murao et al., 2016; Puri et al., 2015). These observations strongly suggest that AD development could be the result of a complex transcriptional regulatory structure modulating regional gene expression (Fitzsimons et al., 2014) supported by clustering of alleles in the molecular signatures identified in the APOE region. Given the functional role of BCAM , NECTIN2 , TOMM40 , APOE , and APOC1 genes and the regulatory activity of variants in these genes, the molecular signatures elucidated in the present study could be associated with increased risk of developing an AD by increasing susceptibility to brain infections (Itzhaki et al., 2016; Porcellini, Carbone, Ianni & Licastro, 2010).…”

Section: Discussionmentioning

confidence: 86%

Apolipoprotein E region molecular signatures of Alzheimer's disease

et al. 2018

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SummaryAlthough the APOE region is the strongest genetic risk factor for Alzheimer's diseases (ADs), its pathogenic role remains poorly understood. Elucidating genetic predisposition to ADs, a subset of age‐related diseases characteristic for postreproductive period, is hampered by the undefined role of evolution in establishing molecular mechanisms of such diseases. This uncertainty is inevitable source of natural‐selection–free genetic heterogeneity in predisposition to ADs. We performed first large‐scale analysis of linkage disequilibrium (LD) structures characterized by 30 polymorphisms from five genes in the APOE 19q13.3 region (BCAM,NECTIN2,TOMM40,APOE, and APOC1) in 2,673 AD‐affected and 16,246 unaffected individuals from five cohorts. Consistent with the undefined role of evolution in age‐related diseases, we found that these structures, being highly heterogeneous, are significantly different in subjects with and without ADs. The pattern of the difference represents molecular signature of AD comprised of single nucleotide polymorphisms (SNPs) from all five genes in the APOE region. Significant differences in LD in subjects with and without ADs indicate SNPs from different genes likely involved in AD pathogenesis. Significant and highly heterogeneous molecular signatures of ADs provide unprecedented insight into complex polygenetic predisposition to ADs in the APOE region. These findings are more consistent with a complex haplotype than with a single genetic variant origin of ADs in this region.

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Section: Discussionmentioning

confidence: 86%

Apolipoprotein E region molecular signatures of Alzheimer's disease

et al. 2018

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“…The pathogenesis of Alzheimer's disease is still not well known, and more studies are needed to further explore the possible pathogenesis [41,42]. Identification of potentially modifiable risk factors for Alzheimer's disease can help us develop some effective interventions to reduce risk of Alzheimer's disease [43,44].…”

Section: Discussionmentioning

confidence: 99%

Inverse Association Between Serum Uric Acid Levels and Alzheimer’s Disease Risk

Hou

et al. 2015

Mol Neurobiol

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The association between Alzheimer's disease and uric acid levels had gained great interest in recent years, but there was still lack of definite evidence. A systematic review and meta-analysis of relevant studies was performed to comprehensively estimate the association. Relevant studies published before October 26, 2014, were searched in PubMed, Embase, and China Biology Medicine (CBM) databases. Study-specific data were combined using random-effects or fixed-effects models of meta-analysis according to between-study heterogeneity. Twenty-four studies (21 case-control and 3 cohort studies) were finally included into the meta-analysis. Those 21 case-control studies included a total of 1128 cases of Alzheimer's disease and 2498 controls without Alzheimer's disease. Those 3 cohort studies included a total of 7327 participants. Meta-analysis showed that patients with Alzheimer's disease had lower levels of uric acid than healthy controls (weighted mean difference (WMD) = -0.77 mg/dl, 95% CI -2.28 to -0.36, P = 0.0002). High serum uric acid levels were significantly associated with decreased risk of Alzheimer's disease (risk ratio (RR) = 0.66, 95% CI 0.52-0.85, P = 0.001). There was low risk of publication bias in the meta-analysis. There is an inverse association between serum uric acid levels and Alzheimer's disease. High serum uric acid level is a protective factor of Alzheimer's disease.

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“…The role of epigenetic regulation in stem cell fate decisions is crucial based on increasing evidence [49,50]. As an HDAC inhibitor, VPA simultaneously regulates the expression of numerous genes by increasing the level of acetylated chromatin [20,51].…”

Section: Discussionmentioning

confidence: 99%

Valproic Acid Arrests Proliferation but Promotes Neuronal Differentiation of Adult Spinal NSPCs from SCI Rats

et al. 2015

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Although the adult spinal cord contains a population of multipotent neural stem/precursor cells (NSPCs) exhibiting the potential to replace neurons, endogenous neurogenesis is very limited after spinal cord injury (SCI) because the activated NSPCs primarily differentiate into astrocytes rather than neurons. Valproic acid (VPA), a histone deacetylase inhibitor, exerts multiple pharmacological effects including fate regulation of stem cells. In this study, we cultured adult spinal NSPCs from chronic compressive SCI rats and treated with VPA. In spite of inhibiting the proliferation and arresting in the G0/G1 phase of NSPCs, VPA markedly promoted neuronal differentiation (β-tubulin III(+) cells) as well as decreased astrocytic differentiation (GFAP(+) cells). Cell cycle regulator p21(Cip/WAF1) and proneural genes Ngn2 and NeuroD1 were increased in the two processes respectively. In vivo, to minimize the possible inhibitory effects of VPA to the proliferation of NSPCs as well as avoid other neuroprotections of VPA in acute phase of SCI, we carried out a delayed intraperitoneal injection of VPA (150 mg/kg/12 h) to SCI rats from day 15 to day 22 after injury. Both of the newborn neuron marker doublecortin and the mature neuron marker neuron-specific nuclear protein were significantly enhanced after VPA treatment in the epicenter and adjacent segments of the injured spinal cord. Although the impaired corticospinal tracks had not significantly improved, Basso-Beattie-Bresnahan scores in VPA treatment group were better than control. Our study provide the first evidence that administration of VPA enhances the neurogenic potential of NSPCs after SCI and reveal the therapeutic value of delayed treatment of VPA to SCI.

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Epigenetic regulation of adult neural stem cells: implications for Alzheimer’s disease

Cited by 54 publications

References 210 publications

Apolipoprotein E region molecular signatures of Alzheimer's disease

Apolipoprotein E region molecular signatures of Alzheimer's disease

Inverse Association Between Serum Uric Acid Levels and Alzheimer’s Disease Risk

Valproic Acid Arrests Proliferation but Promotes Neuronal Differentiation of Adult Spinal NSPCs from SCI Rats

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