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Review
. 2023 Jan 1;13(1):197-230.
doi: 10.7150/thno.79535. eCollection 2023.

Role of primary aging hallmarks in Alzheimer´s disease

Jin Zhao  1   2 , Jisen Huai  1   2
Affiliations
Review

Role of primary aging hallmarks in Alzheimer´s disease

Jin Zhao et al. Theranostics. .

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease, which severely threatens the health of the elderly and causes significant economic and social burdens. The causes of AD are complex and include heritable but mostly aging-related factors. The primary aging hallmarks include genomic instability, telomere wear, epigenetic changes, and loss of protein stability, which play a dominant role in the aging process. Although AD is closely associated with the aging process, the underlying mechanisms involved in AD pathogenesis have not been well characterized. This review summarizes the available literature about primary aging hallmarks and their roles in AD pathogenesis. By analyzing published literature, we attempted to uncover the possible mechanisms of aberrant epigenetic markers with related enzymes, transcription factors, and loss of proteostasis in AD. In particular, the importance of oxidative stress-induced DNA methylation and DNA methylation-directed histone modifications and proteostasis are highlighted. A molecular network of gene regulatory elements that undergoes a dynamic change with age may underlie age-dependent AD pathogenesis, and can be used as a new drug target to treat AD.

Keywords: Aging; Alzheimer's disease; Epigenetics; Molecular neurobiology; Neurodegeneration; Oxidative stress.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Schematic illustration of the hypothesized mechanisms of aberrant gene expression in AD. (left) Downregulation mechanism: DNMTs shift from non-CGI regions to CGI regulatory elements under oxidative stress and catalyze DNA methylation at the damage sites, which recruits MeCP2 and help DNMTs catalyze more DNA methylation thereby resulting in the target gene silencing. (Right) Upregulation mechanism: DNA damage repair induces co-occurence of H3K9ac and/or H3K27ac with H3K4me3, which prevents DNA methylation and represses H3K9me2 inhibitory effect on transcription to overactivate the genes.
Figure 2
Figure 2
Schematic illustration of the hypothesized mechanism of aberrant BDNF expression in AD. DNA methylation at the damage sites recruits MeCP2 and HOTAIR-PRC2-REST complex which prevents coupling of promoter and enhancer resulting in transcription silencing. This event may be involved in the onset of AD.
Figure 3
Figure 3
Schematic illustration of the hypothesized mechanisms of REST expression in ageing and AD. (left) Upregulation mechanism: DNMT1 shifts from non-CGI region to CGI regulatory element under oxidative stress and forms a ß-catenin stabilizing complex to prevent DNA methylation and increase ß-catenin/TCF activity thereby increasing REST transcription. (Right) Downregulation mechanism: DNMT1 is degraded when acetylated by TIP60 and ubiquitinated by UHRF1. which can lead to ß-catenin destabilization. Whereas, MeCP2 can reduce availability of ß-catenin for binding to DNMT1. Both cases will downregulated REST transcription. MOF and p53 prevent SIRT1 expression, which can aggravate DNMT1 degradation.
Figure 4
Figure 4
STRING network of REST and CTCF interaction proteins and REST-CTCF coupling through their interaction partners drawn using Cytoscape (v3.7.1). (A) REST Interaction partners; (B) CTCF interaction partners; (C) REST-CTCF coupling through their interaction partners. CHD8: Chromodomain Helicase DNA Binding Protein 8; CREBBP: CREB Binding Protein; CTDSP1: Carboxy-terminal Domain RNA Polymerase II Polypeptide A Small Phosphatase 1; DDX5: DEAD-Box Helicase 5; EP300: E1A Binding Protein P300; EED: Embyonic Ectoderm Development; FBXW7: F-Box And WD Repeat Domain Containing 7; HDAC2: Histone Deacetylase 2; HIST1H2BD: Histone Cluster 1 H2BD; HIST1H2BH: Histone Cluster 1 H2BH; HIST1H2BJ: HistoneCluster1 H2BJ; HTT: Huntingtin; KAT2A: Lysine Acetyltransferase 2A; KDM1A: Lysine Demethylase 1A: MBD2: Methyl-CpG Binding Domain Protein 2; MTA2: Metastasis Associated 1 Family member2; MYC: Myc Proto-Oncogene, BHLH Transcription factor; NANOG: Nanog Homeobox; NCOR1: Nuclear Receptor Corepressor 1; NIPBL: NIPBL Cohesion Loading factor; NPM1: Nucleophosmin 1; POU5F1: POU Class 5 Homeobox 1; RAD21: RAD21 Cohesion Complex Component; RB1: RB Transcriptional Corepressor 1; RBL2: RB Transcriptional Corepressor Like 2; RCOR1: REST Corepressor 1 (CoREST); SAP30: SIN3A Associated Protein 30; SIN3A: SIN3 Transcrition Regulatory Family Member A; SIN3B: SIN3 Transcrition Regulatory Family Member B; SKP2: S-Phase Kinase Associated Protein 2; SMC3: Structural Maintenance Of Chromosomes 3; SNAI1: Snail Family Transcriptional Repressor 1; STAG2: Stromal Antigen 2; SUZ12: SUZ12 Polycomb Repressive Complex 2 Subunit; TP53: Tumor Protein P53; YY1: YY1 Transcription Factor.
Figure 5
Figure 5
Schematic illustration of correlation between REST, CTCF and their interaction proteins and selected epigenetic markers. (A) Epigenetic markers of the genes related to neural and stem cells are recruited from http://dbtoolkit.cistrome.org, and the mode diagram was drawn using Goplot R package; (B) The mode diagram was drawn using Circlize R package.CHD8: Chromodomain Helicase DNA Binding Protein 8; CREBBP: CREB Binding Protein; CTDSP1: Carboxy-terminal Domain RNA Polymerase II Polypeptide A Small Phosphatase 1; DDX5: DEAD-Box Helicase 5; EP300: E1A Binding Protein P300; EED: Embyonic Ectoderm Development; FBXW7: F-Box And WD Repeat Domain Containing 7; HDAC2: Histone Deacetylase 2; HIST1H2BD: Histone Cluster 1 H2BD; HIST1H2BH: Histone Cluster 1 H2BH; HIST1H2BJ: HistoneCluster1 H2BJ; HTT: Huntingtin; KAT2A: Lysine Acetyltransferase 2A; KDM1A: Lysine Demethylase 1A: MBD2: Methyl-CpG Binding Domain Protein 2; MTA2: Metastasis Associated 1 Family member2; MYC: Myc Proto-Oncogene, BHLH Transcription factor; NANOG: Nanog Homeobox; NCOR1: Nuclear Receptor Corepressor 1; NIPBL: NIPBL Cohesion Loading factor; NPM1: Nucleophosmin 1; POU5F1: POU Class 5 Homeobox 1; RAD21: RAD21 Cohesion Complex Component; RB1: RB Transcriptional Corepressor 1; RBL2: RB Transcriptional Corepressor Like 2; RCOR1: REST Corepressor 1 (CoREST); SAP30: SIN3A Associated Protein 30; SIN3A: SIN3 Transcrition Regulatory Family Member A; SIN3B: SIN3 Transcrition Regulatory Family Member B; SKP2: S-Phase Kinase Associated Protein 2; SMC3: Structural Maintenance Of Chromosomes 3; SNAI1: Snail Family Transcriptional Repressor 1; STAG2: Stromal Antigen 2; SUZ12: SUZ12 Polycomb Repressive Complex 2 Subunit; TP53: Tumor Protein P53; YY1: YY1 Transcription Factor.
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