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The epigenetic dimension of Alzheimer's disease: causal, consequence, or curiosity?

Millan MJ - Dialogues Clin Neurosci (2014)

Bottom Line: In conclusion, epigenetic mechanisms are broadly deregulated in AD mainly upstream, but also downstream, of key pathophysiological processes.Abstract available from the publisher.

View Article: PubMed Central - PubMed

Affiliation: Pole of Innovation in Neuropsychiatry, Institut de Recherche Servier, Croissy-sur-Seine, France.

ABSTRACT
Early-onset, familial Alzheimer's disease (AD) is rare and may be attributed to disease-causinq mutations. By contrast, late onset, sporadic (non-Mendelian) AD is far more prevalent and reflects the interaction of multiple genetic and environmental risk factors, together with the disruption of epigenetic mechanisms controlling gene expression. Accordingly, abnormal patterns of histone acetylation and methylation, as well as anomalies in global and promoter-specific DNA methylation, have been documented in AD patients, together with a deregulation of noncoding RNA. In transgenic mouse models for AD, epigenetic dysfunction is likewise apparent in cerebral tissue, and it has been directly linked to cognitive and behavioral deficits in functional studies. Importantly, epigenetic deregulation interfaces with core pathophysiological processes underlying AD: excess production of Aβ42, aberrant post-translational modification of tau, deficient neurotoxic protein clearance, axonal-synaptic dysfunction, mitochondrial-dependent apoptosis, and cell cycle re-entry. Reciprocally, DNA methylation, histone marks and the levels of diverse species of microRNA are modulated by Aβ42, oxidative stress and neuroinflammation. In conclusion, epigenetic mechanisms are broadly deregulated in AD mainly upstream, but also downstream, of key pathophysiological processes. While some epigenetic shifts oppose the evolution of AD, most appear to drive its progression. Epigenetic changes are of irrefutable importance for AD, but they await further elucidation from the perspectives of pathogenesis, biomarkers and potential treatment.

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Related in: MedlinePlus

Overview of the regulation of multiple species of miRNA by cellular risk factors for Alzheimer's disease. In in vitro studies, a large number of miRs are modulated by exposure to β-amyloid42 (Aβ42) and cellular stressors implicated in the pathophysiology of AD. The direction and magnitude of change will depend upon the stimulus. Note that not all of these miRs have been evaluated in response to each type of stressor, and that many classes of miR remain to be examined.
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DialoguesClinNeurosci-16-373-g002: Overview of the regulation of multiple species of miRNA by cellular risk factors for Alzheimer's disease. In in vitro studies, a large number of miRs are modulated by exposure to β-amyloid42 (Aβ42) and cellular stressors implicated in the pathophysiology of AD. The direction and magnitude of change will depend upon the stimulus. Note that not all of these miRs have been evaluated in response to each type of stressor, and that many classes of miR remain to be examined.

Mentions: As mentioned above, miR-181c is decreased both in AD patients and in transgenic mouse models for AD. Accordingly, its downregulation in vitro by fibrillar Aβ42 is consistent with the notion that the decrease in miR-181c levels seen in AD may be downstream of Aβ42 Figure 2.103,104 Several other classes of microRNA were also downregulated by Aβ42 including miR-9, though not all findings have found a decrease in this microRNA in AD (Table I). Complicating the situation, a recent study found that the effects of soluble forms of Aβ42 differ from those of fibrillar Aβ42 (Figure 2).6 In the latter study, some microRNAs were upregulated by soluble Aβ42 in a N-methyl-D-aspartate (NMDA) receptor-dependent fashion. This is consistent with a role for NMDA receptors in mediating Aβ42 neurotoxicity, perhaps since these receptors are hijacked by Aβ42 in order to enter neurones where it affects miRNAs.106 Conversely, other classes of miRNA were downregulated by soluble Aβ42, including miR-107 which is decreased in AD brain (Table I). This effect of soluble Aβ42 on miR-107 was mimicked by peroxide, indicative of a role for oxidative stress. This is interesting since oxidative stress is a well-known trigger for AD which elicits alterations in the expression of a variety of miRNAs in cellular paradigms (Figure 2).107,108


The epigenetic dimension of Alzheimer's disease: causal, consequence, or curiosity?

Millan MJ - Dialogues Clin Neurosci (2014)

Overview of the regulation of multiple species of miRNA by cellular risk factors for Alzheimer's disease. In in vitro studies, a large number of miRs are modulated by exposure to β-amyloid42 (Aβ42) and cellular stressors implicated in the pathophysiology of AD. The direction and magnitude of change will depend upon the stimulus. Note that not all of these miRs have been evaluated in response to each type of stressor, and that many classes of miR remain to be examined.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214179&req=5

DialoguesClinNeurosci-16-373-g002: Overview of the regulation of multiple species of miRNA by cellular risk factors for Alzheimer's disease. In in vitro studies, a large number of miRs are modulated by exposure to β-amyloid42 (Aβ42) and cellular stressors implicated in the pathophysiology of AD. The direction and magnitude of change will depend upon the stimulus. Note that not all of these miRs have been evaluated in response to each type of stressor, and that many classes of miR remain to be examined.
Mentions: As mentioned above, miR-181c is decreased both in AD patients and in transgenic mouse models for AD. Accordingly, its downregulation in vitro by fibrillar Aβ42 is consistent with the notion that the decrease in miR-181c levels seen in AD may be downstream of Aβ42 Figure 2.103,104 Several other classes of microRNA were also downregulated by Aβ42 including miR-9, though not all findings have found a decrease in this microRNA in AD (Table I). Complicating the situation, a recent study found that the effects of soluble forms of Aβ42 differ from those of fibrillar Aβ42 (Figure 2).6 In the latter study, some microRNAs were upregulated by soluble Aβ42 in a N-methyl-D-aspartate (NMDA) receptor-dependent fashion. This is consistent with a role for NMDA receptors in mediating Aβ42 neurotoxicity, perhaps since these receptors are hijacked by Aβ42 in order to enter neurones where it affects miRNAs.106 Conversely, other classes of miRNA were downregulated by soluble Aβ42, including miR-107 which is decreased in AD brain (Table I). This effect of soluble Aβ42 on miR-107 was mimicked by peroxide, indicative of a role for oxidative stress. This is interesting since oxidative stress is a well-known trigger for AD which elicits alterations in the expression of a variety of miRNAs in cellular paradigms (Figure 2).107,108

Bottom Line: In conclusion, epigenetic mechanisms are broadly deregulated in AD mainly upstream, but also downstream, of key pathophysiological processes.Abstract available from the publisher.

View Article: PubMed Central - PubMed

Affiliation: Pole of Innovation in Neuropsychiatry, Institut de Recherche Servier, Croissy-sur-Seine, France.

ABSTRACT
Early-onset, familial Alzheimer's disease (AD) is rare and may be attributed to disease-causinq mutations. By contrast, late onset, sporadic (non-Mendelian) AD is far more prevalent and reflects the interaction of multiple genetic and environmental risk factors, together with the disruption of epigenetic mechanisms controlling gene expression. Accordingly, abnormal patterns of histone acetylation and methylation, as well as anomalies in global and promoter-specific DNA methylation, have been documented in AD patients, together with a deregulation of noncoding RNA. In transgenic mouse models for AD, epigenetic dysfunction is likewise apparent in cerebral tissue, and it has been directly linked to cognitive and behavioral deficits in functional studies. Importantly, epigenetic deregulation interfaces with core pathophysiological processes underlying AD: excess production of Aβ42, aberrant post-translational modification of tau, deficient neurotoxic protein clearance, axonal-synaptic dysfunction, mitochondrial-dependent apoptosis, and cell cycle re-entry. Reciprocally, DNA methylation, histone marks and the levels of diverse species of microRNA are modulated by Aβ42, oxidative stress and neuroinflammation. In conclusion, epigenetic mechanisms are broadly deregulated in AD mainly upstream, but also downstream, of key pathophysiological processes. While some epigenetic shifts oppose the evolution of AD, most appear to drive its progression. Epigenetic changes are of irrefutable importance for AD, but they await further elucidation from the perspectives of pathogenesis, biomarkers and potential treatment.

Show MeSH
Related in: MedlinePlus