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Open Access 01-12-2024 | Alzheimer's Disease | Research

Histone acetylation in an Alzheimer’s disease cell model promotes homeostatic amyloid-reducing pathways

Authors: Daniel C. Xu, Hanna Sas-Nowosielska, Greg Donahue, Hua Huang, Naemeh Pourshafie, Charly R. Good, Shelley L. Berger

Published in: Acta Neuropathologica Communications | Issue 1/2024

Abstract

Alzheimer’s Disease (AD) is a disorder characterized by cognitive decline, neurodegeneration, and accumulation of amyloid plaques and tau neurofibrillary tangles in the brain. Dysregulation of epigenetic histone modifications may lead to expression of transcriptional programs that play a role either in protecting against disease genesis or in worsening of disease pathology. One such histone modification, acetylation of histone H3 lysine residue 27 (H3K27ac), is primarily localized to genomic enhancer regions and promotes active gene transcription. We previously discovered H3K27ac to be more abundant in AD patient brain tissue compared to the brains of age-matched non-demented controls. In this study, we use iPSC-neurons derived from familial AD patients with an amyloid precursor protein (APP) duplication (APP^Dup neurons) as a model to study the functional effect of lowering CBP/P300 enzymes that catalyze H3K27ac. We found that homeostatic amyloid-reducing genes were upregulated in the APP^Dup neurons compared to non-demented controls. We lowered CBP/P300 to reduce H3K27ac, which led to decreased expression of numerous of these homeostatic amyloid-reducing genes, along with increased extracellular secretion of a toxic amyloid-β species, Aβ(1–42). Our findings suggest that epigenomic histone acetylation, including H3K27ac, drives expression of compensatory genetic programs in response to AD-associated insults, specifically those resulting from APP duplication, and thus may play a role in mitigating AD pathology in neurons.

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Masters CL et al (2015) Alzheimer’s disease. Nat Rev Dis Primer. https://doi.org/10.1038/nrdp.2015.56CrossRef

Glenner GG, Wong CW (2012) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 425:534–539PubMedCrossRef

Murphy MP, LeVine H (2010) Alzheimer’s disease and the amyloid-β peptide. J Alzheimers Dis 19:311–323PubMedPubMedCentralCrossRef

Chen G et al (2017) Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin 38:1205–1235PubMedPubMedCentralCrossRef

Karran E, De Strooper B (2022) The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nat Rev Drug Discov 21:306–318PubMedCrossRef

Lee VM-Y, Goedert M, Trojanowski JQ (2001) Neurodegenerative Tauopathies. Annu Rev Neurosci 24:1121–1159PubMedCrossRef

Busche MA, Hyman BT (2020) Synergy between amyloid-β and tau in Alzheimer’s disease. Nat Neurosci 23:1183–1193PubMedCrossRef

Bloom GS (2014) Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71:505PubMedCrossRef

Nativio R et al (2018) Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease. Nat Neurosci 21:497–505PubMedPubMedCentralCrossRef

10.

Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y (1996) The Transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87:953–959PubMedCrossRef

11.

Raisner R et al (2018) Enhancer activity requires CBP/P300 bromodomain-dependent histone H3K27 acetylation. Cell Rep 24:1722–1729PubMedCrossRef

12.

Tie F et al (2009) CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing. Development 136:3131–3141PubMedPubMedCentralCrossRef

13.

Beacon TH et al (2021) The dynamic broad epigenetic (H3K4me3, H3K27ac) domain as a mark of essential genes. Clin Epigenetics 13:138PubMedPubMedCentralCrossRef

14.

Creyghton MP et al (2010) Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci 107:21931–21936PubMedPubMedCentralCrossRef

15.

Nativio R et al (2020) An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease. Nat Genet 52:1024–1035PubMedPubMedCentralCrossRef

16.

Marzi SJ et al (2018) A histone acetylome-wide association study of Alzheimer’s disease identifies disease-associated H3K27ac differences in the entorhinal cortex. Nat Neurosci 21:1618–1627PubMedCrossRef

17.

Zhang Y et al (2013) Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron 78:785–798PubMedPubMedCentralCrossRef

18.

Fernandopulle MS et al (2018) Transcription factor-mediated differentiation of human iPSCs into neurons: rapid differentiation of iPSCs into neurons. Curr Protoc Cell Biol 79:e51PubMedPubMedCentralCrossRef

19.

Wang C et al (2017) Scalable production of iPSC-derived human neurons to identify tau-lowering compounds by high-content screening. Stem Cell Rep 9:1221–1233CrossRef

20.

Abud EM et al (2017) iPSC-derived human microglia-like cells to study neurological diseases. Neuron 94:278-293.e9PubMedPubMedCentralCrossRef

21.

Israel MA et al (2012) Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482:216–220PubMedPubMedCentralCrossRef

22.

Lin Y-T et al (2018) APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98:1141-1154.e7PubMedPubMedCentralCrossRef

23.

Tian R et al (2019) CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons. Neuron 104:239-255.e12PubMedPubMedCentralCrossRef

24.

Chen M et al (2020) Rapid generation of regionally specified CNS neurons by sequential patterning and conversion of human induced pluripotent stem cells. Stem Cell Res 48:101945PubMedCrossRef

25.

Liu Y, Labosky PA (2008) Regulation of embryonic stem cell self-renewal and pluripotency by Foxd3. Stem Cells 26:2475–2484PubMedCrossRef

26.

Lemmens M et al (2023) Identification of marker genes to monitor residual iPSCs in iPSC-derived products. Cytotherapy 25:59–67PubMedCrossRef

27.

Herwig R, Hardt C, Lienhard M, Kamburov A (2016) Analyzing and interpreting genome data at the network level with ConsensusPathDB. Nat Protoc 11:1889–1907PubMedCrossRef

28.

Kamburov A, Wierling C, Lehrach H, Herwig R (2009) ConsensusPathDB—a database for integrating human functional interaction networks. Nucleic Acids Res 37:D623–D628PubMedCrossRef

29.

Griffin JWD, Bradshaw PC (2017) Amino acid catabolism in Alzheimer’s disease brain: friend or foe? Oxid Med Cell Longev 2017:1–15CrossRef

30.

Behl T et al (2021) Role of monoamine oxidase activity in Alzheimer’s disease: an insight into the therapeutic potential of inhibitors. Molecules 26:3724PubMedPubMedCentralCrossRef

31.

Cairns DM, Itzhaki RF, Kaplan DL (2022) Potential involvement of varicella zoster virus in Alzheimer’s disease via reactivation of quiescent herpes simplex virus type 1. J Alzheimers Dis 88:1189–1200PubMedCrossRef

32.

Tiwari D, Mittal N, Jha HC (2022) Unraveling the links between neurodegeneration and Epstein-Barr virus-mediated cell cycle dysregulation. Curr Res Neurobiol 3:100046PubMedPubMedCentralCrossRef

33.

Kanehisa M, Goto S KEGG: Kyoto Encyclopedia of Genes and Genomes

34.

Jin Q et al (2011) Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation: histone acetylation and gene activation. EMBO J 30:249–262PubMedCrossRef

35.

Martire S, Nguyen J, Sundaresan A, Banaszynski LA (2020) Differential contribution of p300 and CBP to regulatory element acetylation in mESCs. BMC Mol Cell Biol 21:55PubMedPubMedCentralCrossRef

36.

Bartlett DW (2006) Insights into the kinetics of siRNA-mediated gene silencing from live-cell and live-animal bioluminescent imaging. Nucleic Acids Res 34:322–333PubMedPubMedCentralCrossRef

37.

Ashburner M et al (2000) Gene ontology: tool for the unification of biology. Nat Genet 25:25–29PubMedPubMedCentralCrossRef

38.

Yu G, Wang L-G, Han Y, He Q-Y (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS J Integr Biol 16:284–287CrossRef

39.

Wu T et al (2021) clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. The Innovation 2:100141PubMedPubMedCentralCrossRef

40.

Maddox SA, Watts CS, Schafe GE (2013) p300/CBP histone acetyltransferase activity is required for newly acquired and reactivated fear memories in the lateral amygdala. Learn Mem 20:109–119PubMedPubMedCentralCrossRef

41.

Chatterjee S et al (2013) A novel activator of CBP/p300 acetyltransferases promotes neurogenesis and extends memory duration in adult mice. J Neurosci 33:10698–10712PubMedPubMedCentralCrossRef

42.

Bean DM et al (2014) esyN: network building, sharing and publishing. PLoS ONE 9:e106035PubMedPubMedCentralCrossRef

43.

Stark C et al (2006) BioGRID: a general repository for interaction datasets. Nucleic Acids Res 34:D535-539PubMedCrossRef

44.

Wang L et al (2012) Epidermal growth factor receptor is a preferred target for treating Amyloid-β–induced memory loss. Proc Natl Acad Sci 109:16743–16748PubMedPubMedCentralCrossRef

45.

Chiang H-C, Wang L, Xie Z, Yau A, Zhong Y (2010) PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila. Proc Natl Acad Sci 107:7060–7065PubMedPubMedCentralCrossRef

46.

Wang L, Liang B, Zhong Y (2013) Reduced EGFR level potentially mediates the Aβ42-induced neuronal loss in transgenic fruit fly and mouse. Protein Cell 4:647–649PubMedPubMedCentralCrossRef

47.

Nigam SM et al (2017) Exercise and BDNF reduce Aβ production by enhancing α-secretase processing of APP. J Neurochem 142:286–296PubMedPubMedCentralCrossRef

48.

Baranowski BJ, Hayward GC, Marko DM, MacPherson REK (2021) Examination of BDNF Treatment on BACE1 Activity and Acute Exercise on Brain BDNF Signaling. Front Cell Neurosci 15:665867PubMedPubMedCentralCrossRef

49.

Matrone C, Ciotti MT, Mercanti D, Marolda R, Calissano P (2008) NGF and BDNF signaling control amyloidogenic route and Aβ production in hippocampal neurons. Proc Natl Acad Sci 105:13139–13144PubMedPubMedCentralCrossRef

50.

Sakae N et al (2016) ABCA7 deficiency accelerates amyloid-β generation and Alzheimer’s neuronal pathology. J Neurosci 36:3848–3859PubMedPubMedCentralCrossRef

51.

Aikawa T, Holm M-L, Kanekiyo T (2018) ABCA7 and pathogenic pathways of Alzheimer’s disease. Brain Sci 8:27PubMedPubMedCentralCrossRef

52.

Bhattacharyya R, Teves CAF, Long A, Hofert M, Tanzi RE (2022) The neuronal-specific isoform of BIN1 regulates β-secretase cleavage of APP and Aβ generation in a RIN3-dependent manner. Sci Rep 12:3486PubMedPubMedCentralCrossRef

53.

Miyagawa T et al (2016) BIN1 regulates BACE1 intracellular trafficking and amyloid-β production. Hum Mol Genet. https://doi.org/10.1093/hmg/ddw146CrossRefPubMed

54.

Ubelmann F et al (2017) Bin1 and CD 2 AP polarise the endocytic generation of beta-amyloid. EMBO Rep 18:102–122PubMedCrossRef

55.

Yin R-H, Yu J-T, Tan L (2015) The role of SORL1 in Alzheimer’s disease. Mol Neurobiol 51:909–918PubMedCrossRef

56.

Terni B, Ferrer I (2015) Abnormal expression and distribution of MMP2 at initial stages of Alzheimer’s disease-related pathology. J Alzheimers Dis 46:461–469PubMedCrossRef

57.

Gallwitz L et al (2022) Cathepsin D: analysis of its potential role as an amyloid beta degrading protease. Neurobiol Dis 175:105919PubMedCrossRef

58.

Funalot B et al (2004) Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer’s disease. Mol Psychiatry 9:1122–1128PubMedCrossRef

59.

Miners S et al (2012) Genetic variation in MME in relation to neprilysin protein and enzyme activity, Aβ levels, and Alzheimer’s disease risk. Int J Mol Epidemiol Genet 3:30–38PubMedPubMedCentral

60.

Grimm MOW et al (2013) Neprilysin and Aβ clearance: impact of the APP intracellular domain in NEP regulation and implications in Alzheimer’s disease. Front Aging Neurosci 5:98PubMedPubMedCentralCrossRef

61.

Tucker HM et al (2000) The plasmin system is induced by and degrades amyloid-β aggregates. J Neurosci 20:3937–3946PubMedPubMedCentralCrossRef

62.

Tanzi RE, Bertram L (2005) Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 120:545–555PubMedCrossRef

63.

Nishitsuji K, Hosono T, Uchimura K, Michikawa M (2011) Lipoprotein lipase is a novel amyloid beta (Abeta)-binding protein that promotes glycosaminoglycan-dependent cellular uptake of Abeta in astrocytes. J Biol Chem 286:6393–6401PubMedCrossRef

64.

Deane R et al (2004) LRP/Amyloid β-peptide interaction mediates differential brain efflux of Aβ isoforms. Neuron 43:333–344PubMedCrossRef

65.

Fernandez CG, Hamby ME, McReynolds ML, Ray WJ (2019) The role of APOE4 in disrupting the homeostatic functions of astrocytes and microglia in aging and Alzheimer’s disease. Front Aging Neurosci 11:14PubMedPubMedCentralCrossRef

66.

Huang Y-WA, Zhou B, Nabet AM, Wernig M, Südhof TC (2019) Differential signaling mediated by ApoE2, ApoE3, and ApoE4 in human neurons parallels Alzheimer’s disease risk. J Neurosci 39:7408–7427PubMedPubMedCentralCrossRef

67.

Rodriguez GA, Tai LM, LaDu M, Rebeck G (2014) Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J Neuroinflammation 11:111PubMedPubMedCentralCrossRef

68.

Pirooznia SK et al (2012) Tip60 HAT activity mediates app induced lethality and apoptotic cell death in the CNS of a drosophila Alzheimer’s disease model. PLoS ONE 7:e41776PubMedPubMedCentralCrossRef

69.

Johnson AA, Sarthi J, Pirooznia SK, Reube W, Elefant F (2013) Increasing Tip60 HAT levels rescues axonal transport defects and associated behavioral phenotypes in a drosophila Alzheimer’s disease model. J Neurosci 33:7535–7547PubMedPubMedCentralCrossRef

70.

Gräff J et al (2012) An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483:222–226PubMedPubMedCentralCrossRef

71.

Lin Y et al (2023) ACSS2-dependent histone acetylation improves cognition in mouse model of Alzheimer’s disease. Mol Neurodegener 18:47PubMedPubMedCentralCrossRef

72.

Mews P et al (2017) Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature 546:381–386PubMedPubMedCentralCrossRef

73.

Alexander DC et al (2022) Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation. Proc Natl Acad Sci 119:e2114758119PubMedPubMedCentralCrossRef

74.

Rodrigues DA, Pinheiro PDSM, Sagrillo FS, Bolognesi ML, Fraga CAM (2020) Histone deacetylases as targets for the treatment of neurodegenerative disorders: challenges and future opportunities. Med Res Rev 40:2177–2211PubMedCrossRef

75.

Valor L, Viosca J, Lopez-Atalaya J, Barco A (2013) Lysine acetyltransferases CBP and p300 as therapeutic targets in cognitive and neurodegenerative disorders. Curr Pharm Des 19:5051–5064PubMedPubMedCentralCrossRef

76.

Wang H, Eckel RH (2012) Lipoprotein lipase in the brain and nervous system. Annu Rev Nutr 32:147–160PubMedPubMedCentralCrossRef

77.

Zhou F et al (2020) Selective inhibition of CBP/p300 HAT by A-485 results in suppression of lipogenesis and hepatic gluconeogenesis. Cell Death Dis 11:745PubMedPubMedCentralCrossRef

78.

Ries M, Sastre M (2016) Mechanisms of Aβ clearance and degradation by glial cells. Front Aging Neurosci 8:160PubMedPubMedCentralCrossRef

79.

Mansour H, Fawzy H, El-Khatib A, Khattab M (2022) Repurposed anti-cancer epidermal growth factor receptor inhibitors: mechanisms of neuroprotective effects in Alzheimer’s disease. Neural Regen Res 17:1913PubMedPubMedCentralCrossRef

80.

Choi H-J, Jeong YJ, Kim J, Hoe H-S (2023) EGFR is a potential dual molecular target for cancer and Alzheimer’s disease. Front Pharmacol 14:1238639PubMedPubMedCentralCrossRef

81.

Chen Y-J et al (2019) Anti-inflammatory effect of afatinib (an EGFR-TKI) on OGD-induced neuroinflammation. Sci Rep 9:2516PubMedPubMedCentralCrossRef

82.

Thomas R et al (2016) Epidermal growth factor prevents APOE4 and amyloid-beta-induced cognitive and cerebrovascular deficits in female mice. Acta Neuropathol Commun 4:111PubMedPubMedCentralCrossRef

83.

Ramamurthy E et al (2023) Cell type-specific histone acetylation profiling of Alzheimer’s disease subjects and integration with genetics. Front Mol Neurosci 15:948456PubMedPubMedCentralCrossRef

84.

Cohen TJ et al (2011) The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun 2:252PubMedCrossRef

85.

Tracy TE et al (2016) Acetylated Tau obstructs KIBRA-mediated signaling in synaptic plasticity and promotes tauopathy-related memory loss. Neuron 90:245–260PubMedPubMedCentralCrossRef

86.

Vieira PA, Korzus E (2015) CBP-Dependent memory consolidation in the prefrontal cortex supports object-location learning: THE m PFC SUPPORTS SPATIAL RECOGNITION. Hippocampus 25:1532–1540PubMedPubMedCentralCrossRef

87.

Chen G et al (2011) Chemically defined conditions for human iPSC derivation and culture. Nat Methods 8:424–429PubMedPubMedCentralCrossRef

88.

Chomczynski P, Mackey K (1995) Short technical reports. Modification of the TRI reagent procedure for isolation of RNA from polysaccharide- and proteoglycan-rich sources. Biotechniques 19:942–945PubMed

89.

Dou Z et al (2015) Autophagy mediates degradation of nuclear lamina. Nature 527:105–109PubMedPubMedCentralCrossRef

90.

Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550PubMedPubMedCentralCrossRef

91.

Ritchie ME et al (2015) Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47–e47PubMedPubMedCentralCrossRef

92.

Luo W, Brouwer C (2013) Pathview: an R/Bioconductor package for pathway-based data integration and visualization. Bioinformatics 29:1830–1831PubMedPubMedCentralCrossRef

93.

Jain A, Tuteja G (2019) TissueEnrich: tissue-specific gene enrichment analysis. Bioinformatics 35:1966–1967PubMedCrossRef

94.

Blighe K, Rana S, Lewis M (2023) EnhancedVolcano: Publication-ready volcano plots with enhanced colouring and labeling

95.

Korotkevich, G. et al. (2016) Fast gene set enrichment analysis. https://doi.org/10.1101/060012

96.

Subramanian A et al (2005) Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci 102:15545–15550PubMedPubMedCentralCrossRef

97.

Mootha VK et al (2003) PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273PubMedCrossRef

98.

Wickham, H. ggplot2: Elegant Graphics for Data Analysis. (Springer International Publishing : Imprint: Springer, 2016). doi: https://doi.org/10.1007/978-3-319-24277-4.

99.

Ahlmann-Eltze, C. & Patil, I. ggsignif: R Package for Displaying Significance Brackets for ‘ggplot2’. https://osf.io/7awm6 (2021)

100.

Wang M, Zhao Y, Zhang B (2015) Efficient test and visualization of multi-set intersections. Sci Rep 5:16923PubMedPubMedCentralCrossRef

Title: Histone acetylation in an Alzheimer’s disease cell model promotes homeostatic amyloid-reducing pathways
Authors: Daniel C. Xu
Hanna Sas-Nowosielska
Greg Donahue
Hua Huang
Naemeh Pourshafie
Charly R. Good
Shelley L. Berger
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Alzheimer's Disease
Alzheimer's Disease
Published in: Acta Neuropathologica Communications / Issue 1/2024
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-023-01696-6

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Histone acetylation in an Alzheimer’s disease cell model promotes homeostatic amyloid-reducing pathways

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