Disruption of neocortical histone H3 homeostasis by soluble Aβ: Implications for Alzheimer's disease

Christina Unger Lithner; Pascale N. Lacor; Wei Qin Zhao; Tamanna Mustafiz; William L. Klein; J. David Sweatt; Caterina M. Hernandez

doi:10.1016/j.neurobiolaging.2012.12.028

Disruption of neocortical histone H3 homeostasis by soluble Aβ: Implications for Alzheimer's disease

Christina Unger Lithner, Pascale N. Lacor, Wei Qin Zhao, Tamanna Mustafiz, William L. Klein, J. David Sweatt, Caterina M. Hernandez

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

Abstract

Amyloid-β peptide (Aβ) fragment misfolding may play a crucial role in the progression of Alzheimer's disease (AD) pathophysiology as well as epigenetic mechanisms at the DNA and histone level. We hypothesized that histone H3 homeostasis is disrupted in association with the appearance of soluble Aβ at an early stage in AD progression. We identified, localized, and compared histone H3 modifications in multiple model systems (neural-like SH-SY5Y, primary neurons, Tg2576 mice, and AD neocortex), and narrowed our focus to investigate 3 key motifs associated with regulating transcriptional activation and inhibition: acetylated lysine 14, phosphorylated serine 10 and dimethylated lysine 9. Our results invitro and invivo indicate that multimeric soluble Aβ may be a potent signaling molecule indirectly modulating the transcriptional activity of DNA by modulating histone H3 homeostasis. These findings reveal potential loci of transcriptional disruption relevant to AD. Identifying genes that undergo significant epigenetic alterations in response to Aβ could aid in the understanding of the pathogenesis of AD, as well as suggesting possible new treatment strategies.

Original language	English (US)
Pages (from-to)	2081-2090
Number of pages	10
Journal	Neurobiology of Aging
Volume	34
Issue number	9
DOIs	https://doi.org/10.1016/j.neurobiolaging.2012.12.028
State	Published - Sep 2013
Externally published	Yes

Keywords

Alzheimer's disease
Amyloid-β peptide/protein
Dendritic spine
Drebrin
Epigenetics
Histone H3
Histone acetylation
Histone methylation
Neocortex
Soluble Aβ/Aβ-derived diffusible ligand (ADDL)
Tg2576 transgenic mouse model

ASJC Scopus subject areas

General Neuroscience
Aging
Clinical Neurology
Developmental Biology
Geriatrics and Gerontology

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10.1016/j.neurobiolaging.2012.12.028

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@article{de3caa5512e74b359e0fde75b51dc197,

title = "Disruption of neocortical histone H3 homeostasis by soluble Aβ: Implications for Alzheimer's disease",

abstract = "Amyloid-β peptide (Aβ) fragment misfolding may play a crucial role in the progression of Alzheimer's disease (AD) pathophysiology as well as epigenetic mechanisms at the DNA and histone level. We hypothesized that histone H3 homeostasis is disrupted in association with the appearance of soluble Aβ at an early stage in AD progression. We identified, localized, and compared histone H3 modifications in multiple model systems (neural-like SH-SY5Y, primary neurons, Tg2576 mice, and AD neocortex), and narrowed our focus to investigate 3 key motifs associated with regulating transcriptional activation and inhibition: acetylated lysine 14, phosphorylated serine 10 and dimethylated lysine 9. Our results invitro and invivo indicate that multimeric soluble Aβ may be a potent signaling molecule indirectly modulating the transcriptional activity of DNA by modulating histone H3 homeostasis. These findings reveal potential loci of transcriptional disruption relevant to AD. Identifying genes that undergo significant epigenetic alterations in response to Aβ could aid in the understanding of the pathogenesis of AD, as well as suggesting possible new treatment strategies.",

keywords = "Alzheimer's disease, Amyloid-β peptide/protein, Dendritic spine, Drebrin, Epigenetics, Histone H3, Histone acetylation, Histone methylation, Neocortex, Soluble Aβ/Aβ-derived diffusible ligand (ADDL), Tg2576 transgenic mouse model",

author = "Lithner, {Christina Unger} and Lacor, {Pascale N.} and Zhao, {Wei Qin} and Tamanna Mustafiz and Klein, {William L.} and Sweatt, {J. David} and Hernandez, {Caterina M.}",

note = "Funding Information: This research was supported by the American Psychological Association , UAB Career Development Award and Alzheimer's Research Center Pilot Project Grant (C.M.H.), Evelyn McKnight Brain Research Foundation , and Ellison Medical Foundation Senior Scholar Award in Aging (J.D.S.), National Institutes of Health grants MH57014 , MH091122 , and NS057098 (J.D.S.), AG031722 , AG018877 and AG022547 (W.K.L. and P.N.L.), The Dementia Association , Sweden, Swedish Research Council (05817), the Swedish Brain Foundation , Gun and Bertil Stohne's Foundation , the Old Servants' Foundation , Loo and Hans Osterman's Foundation , Ragnhild and Einar Lundstr{\"o}ms Minne and the Karolinska Institutet-Johnson & Johnson Agreement (C.U.L.), American Health Assistance Foundation A2006-092 (W.K.L. and P.N.L.). Research was done when W.Q.Z. was employed by Northwestern University and Acumen Pharmaceuticals, Inc. W.Q.Z. is currently employed by NIH. The opinions expressed in this article are the authors' own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. We thank Professor Agneta Nordberg, Karolinska Institutet, Sweden, for generous use of laboratory space to conduct cell culture experiments and for sharing brain tissue obtained through the NBB. ",

year = "2013",

month = sep,

doi = "10.1016/j.neurobiolaging.2012.12.028",

language = "English (US)",

volume = "34",

pages = "2081--2090",

journal = "Neurobiology of Aging",

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number = "9",

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T1 - Disruption of neocortical histone H3 homeostasis by soluble Aβ

T2 - Implications for Alzheimer's disease

AU - Lithner, Christina Unger

AU - Lacor, Pascale N.

AU - Zhao, Wei Qin

AU - Mustafiz, Tamanna

AU - Klein, William L.

AU - Sweatt, J. David

AU - Hernandez, Caterina M.

N1 - Funding Information: This research was supported by the American Psychological Association , UAB Career Development Award and Alzheimer's Research Center Pilot Project Grant (C.M.H.), Evelyn McKnight Brain Research Foundation , and Ellison Medical Foundation Senior Scholar Award in Aging (J.D.S.), National Institutes of Health grants MH57014 , MH091122 , and NS057098 (J.D.S.), AG031722 , AG018877 and AG022547 (W.K.L. and P.N.L.), The Dementia Association , Sweden, Swedish Research Council (05817), the Swedish Brain Foundation , Gun and Bertil Stohne's Foundation , the Old Servants' Foundation , Loo and Hans Osterman's Foundation , Ragnhild and Einar Lundströms Minne and the Karolinska Institutet-Johnson & Johnson Agreement (C.U.L.), American Health Assistance Foundation A2006-092 (W.K.L. and P.N.L.). Research was done when W.Q.Z. was employed by Northwestern University and Acumen Pharmaceuticals, Inc. W.Q.Z. is currently employed by NIH. The opinions expressed in this article are the authors' own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. We thank Professor Agneta Nordberg, Karolinska Institutet, Sweden, for generous use of laboratory space to conduct cell culture experiments and for sharing brain tissue obtained through the NBB.

PY - 2013/9

Y1 - 2013/9

N2 - Amyloid-β peptide (Aβ) fragment misfolding may play a crucial role in the progression of Alzheimer's disease (AD) pathophysiology as well as epigenetic mechanisms at the DNA and histone level. We hypothesized that histone H3 homeostasis is disrupted in association with the appearance of soluble Aβ at an early stage in AD progression. We identified, localized, and compared histone H3 modifications in multiple model systems (neural-like SH-SY5Y, primary neurons, Tg2576 mice, and AD neocortex), and narrowed our focus to investigate 3 key motifs associated with regulating transcriptional activation and inhibition: acetylated lysine 14, phosphorylated serine 10 and dimethylated lysine 9. Our results invitro and invivo indicate that multimeric soluble Aβ may be a potent signaling molecule indirectly modulating the transcriptional activity of DNA by modulating histone H3 homeostasis. These findings reveal potential loci of transcriptional disruption relevant to AD. Identifying genes that undergo significant epigenetic alterations in response to Aβ could aid in the understanding of the pathogenesis of AD, as well as suggesting possible new treatment strategies.

AB - Amyloid-β peptide (Aβ) fragment misfolding may play a crucial role in the progression of Alzheimer's disease (AD) pathophysiology as well as epigenetic mechanisms at the DNA and histone level. We hypothesized that histone H3 homeostasis is disrupted in association with the appearance of soluble Aβ at an early stage in AD progression. We identified, localized, and compared histone H3 modifications in multiple model systems (neural-like SH-SY5Y, primary neurons, Tg2576 mice, and AD neocortex), and narrowed our focus to investigate 3 key motifs associated with regulating transcriptional activation and inhibition: acetylated lysine 14, phosphorylated serine 10 and dimethylated lysine 9. Our results invitro and invivo indicate that multimeric soluble Aβ may be a potent signaling molecule indirectly modulating the transcriptional activity of DNA by modulating histone H3 homeostasis. These findings reveal potential loci of transcriptional disruption relevant to AD. Identifying genes that undergo significant epigenetic alterations in response to Aβ could aid in the understanding of the pathogenesis of AD, as well as suggesting possible new treatment strategies.

KW - Alzheimer's disease

KW - Amyloid-β peptide/protein

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KW - Histone H3

KW - Histone acetylation

KW - Histone methylation

KW - Neocortex

KW - Soluble Aβ/Aβ-derived diffusible ligand (ADDL)

KW - Tg2576 transgenic mouse model

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Disruption of neocortical histone H3 homeostasis by soluble Aβ: Implications for Alzheimer's disease

Abstract

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ASJC Scopus subject areas

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