Aberrant intracellular localization of H3k4me3 demonstrates an early epigenetic phenomenon in Alzheimer's disease

Mastroeni, Diego; Delvaux, Elaine; Nolz, Jennifer; Tan, Yuyan; Grover, Andrew; Oddo, Salvatore; Coleman, Paul D.

doi:10.1016/j.neurobiolaging.2015.08.017

Cited by 49 publications

(50 citation statements)

References 42 publications

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“…This cytoplasmic distribution of H3K9me3 was exacerbated in AT8-positive neurons from AD brains in which H3K9me3 labelling was exclusively detected in the cytoplasm. Recently, aberrant cytoplasmic localization was described in hippocampal neurons from AD brains for another trimethylated form of H3, H3K4me343, raising the issue concerning the potential effects of the presence of cytoplasmic histones in neuronal cells with respect to cellular signalling and innate immunity, as it has been reported in non-neuronal cells44.…”

Section: Discussionmentioning

confidence: 98%

Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin

Mansuroglu¹,

Benhelli-Mokrani²,

Marcato³

et al. 2016

Sci Rep

110

109

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Pericentromeric heterochromatin (PCH) gives rise to highly dense chromatin sub-structures rich in the epigenetic mark corresponding to the trimethylated form of lysine 9 of histone H3 (H3K9me3) and in heterochromatin protein 1α (HP1α), which regulate genome expression and stability. We demonstrate that Tau, a protein involved in a number of neurodegenerative diseases including Alzheimer’s disease (AD), binds to and localizes within or next to neuronal PCH in primary neuronal cultures from wild-type mice. Concomitantly, we show that the clustered distribution of H3K9me3 and HP1α, two hallmarks of PCH, is disrupted in neurons from Tau-deficient mice (KOTau). Such altered distribution of H3K9me3 that could be rescued by overexpressing nuclear Tau protein was also observed in neurons from AD brains. Moreover, the expression of PCH non-coding RNAs, involved in PCH organization, was disrupted in KOTau neurons that displayed an abnormal accumulation of stress-induced PCH DNA breaks. Altogether, our results demonstrate a new physiological function of Tau in directly regulating neuronal PCH integrity that appears disrupted in AD neurons.

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Section: Discussionmentioning

confidence: 98%

Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin

Mansuroglu¹,

Benhelli-Mokrani²,

Marcato³

et al. 2016

Sci Rep

110

109

View full text Add to dashboard Cite

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“…We have previously proposed a model of AD pathophysiology in which oligomeric Aβ disrupts the exchange of molecules between the cell nucleus and the cytoplasm [57]. Disruption of this exchange then jeopardizes critical functions of the cell leading to selected phenotypes of AD [58].…”

Section: Discussionmentioning

confidence: 99%

Nuclear but not mitochondrial‐encoded oxidative phosphorylation genes are altered in aging, mild cognitive impairment, and Alzheimer's disease

Mastroeni

Khdour

Delvaux

et al. 2016

Alzheimer's & Dementia

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Introduction We have comprehensively described the expression profiles of mitochondrial DNA and nuclear DNA genes that encode subunits of the respiratory oxidative phosphorylation (OXPHOS) complexes (I–V) in the hippocampus from young controls, age matched, mild cognitively impaired (MCI), and Alzheimer’s disease (AD) subjects. Methods Hippocampal tissues from 44 non-AD controls (NC), 10 amnestic MCI, and 18 AD cases were analyzed on Affymetrix Hg-U133 plus 2.0 arrays. Results The microarray data revealed significant down regulation in OXPHOS genes in AD, particularly those encoded in the nucleus. In contrast, there was up regulation of the same gene(s) in MCI subjects compared to AD and ND cases. No significant differences were observed in mtDNA genes identified in the array between AD, ND, and MCI subjects except one mt-ND6. Discussion Our findings suggest that restoration of the expression of nuclear-encoded OXPHOS genes in aging could be a viable strategy for blunting AD progression.

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“…(Bennett, et al, 2015,Lardenoije, et al, 2015,Mastroeni, et al, 2010,Mastroeni, et al, 2011,Yu, et al, 2015). Such changes have been linked to changes in AD-related mitochondrial energy metabolism(Salminen, et al, 2015) and also synaptic function(Berchtold, et al, 2013,Berchtold, et al, 2014,Mastroeni, et al, 2015). Downregulation of important synaptic genes could significantly alter synaptic homeostasis and plasticity in both normal aging and AD leading to subtle changes in cognition that might be difficult to detect early in the disease progression.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress and hippocampal synaptic protein levels in elderly cognitively intact individuals with Alzheimer's disease pathology

Scheff

Ansari

Mufson

2016

Neurobiology of Aging

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Neuritic amyloid plaques and neurofibrillary tangles are hallmarks of Alzheimer's disease (AD) and are major components used for the clinical diagnosis of this disorder. However, many individuals with no cognitive impairment (NCI) also present at autopsy with high levels of these AD pathologic hallmarks. In this study, we evaluated 15 autopsy cases from NCI individuals with high levels of AD-like pathology (HPNCI) and compared them to age- and postmortem-matched cohorts of individuals with amnestic mild cognitive impairment (aMCI) and NCI cases with low AD-like pathology (LPNCI). Individuals classified as HPNCI or aMCI had a significant loss of both presynaptic and postsynaptic proteins in the hippocampus compared to the LPNCI cohort. In addition, these two groups had a significant increase in three different markers of oxidative stress compared to the LPNCI group. The changes in levels of synaptic proteins strongly associated with levels of oxidative stress. These data suggest that cognitively older subjects without dementia but with increased levels of AD-like pathology may represent a very early preclinical stage of AD.

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Aberrant intracellular localization of H3k4me3 demonstrates an early epigenetic phenomenon in Alzheimer's disease

Cited by 49 publications

References 42 publications

Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin

Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin

Nuclear but not mitochondrial‐encoded oxidative phosphorylation genes are altered in aging, mild cognitive impairment, and Alzheimer's disease

Oxidative stress and hippocampal synaptic protein levels in elderly cognitively intact individuals with Alzheimer's disease pathology

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