- Review
- Open access
- Published:
Novel histone post-translational modifications in Alzheimer’s disease: current advances and implications
Clinical Epigenetics volume 16, Article number: 39 (2024)
Abstract
Alzheimer’s disease (AD) has a complex pathogenesis, and multiple studies have indicated that histone post-translational modifications, especially acetylation, play a significant role in it. With the development of mass spectrometry and proteomics, an increasing number of novel HPTMs, including lactoylation, crotonylation, β-hydroxybutyrylation, 2-hydroxyisobutyrylation, succinylation, and malonylation, have been identified. These novel HPTMs closely link substance metabolism to gene regulation, and an increasing number of relevant studies on the relationship between novel HPTMs and AD have become available. This review summarizes the current advances and implications of novel HPTMs in AD, providing insight into the deeper pathogenesis of AD and the development of novel drugs.
Highlights
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Histone post-translational modifications (HPTMs) have been shown to be involved in the pathological mechanism of Alzheimer’s disease (AD) in a variety of models.
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The relationship between novel HPTMs and diseases has become a research hotspot.
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Studies hinted that novel HPTMs are involved in the pathogenesis of AD.
Introduction
Alzheimer’s disease (AD), a degenerative disease of the central nervous system, is characterized by progressive cognitive and behavioral impairment, and it primarily occurs in the elderly and pre-elderly [1]. The incidence, prevalence, mortality, and morbidity rates of AD are not optimistic [2]. Multiple-related mechanisms contribute to the pathogenesis of AD, including interconnected networks of genetic, epigenetic, biological, and environment factors [3]. Deposition of misfolded amyloid beta (Aβ) peptides and the microtubule-associated protein tau are important pathological features of AD [1, 4]. Neuroinflammation and the activation and action of innate immune cells are also involved in the pathophysiological mechanisms of AD [5]. Aβ and tau are the most promising prospective drug targets for AD treatment [6]. Currently, drugs approved for AD treatment mainly provide symptomatic treatment, and their effects are often unsatisfactory [6]. The U.S. food and drug administration (FDA) has approved early-stage drugs for AD, such as anticholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, which provide only short-term symptom improvement without preventing disease progression [7]. In recent years, with the expansion of research field, amyloid-related therapy has emerged as an important trend in the future clinical trials of new drugs [8]. The FDA has approved Aducanumab and Lecanemab, which are antibodies against amyloids that may prevent or reverse the progression of AD [8]. However, this novel amyloid-related therapy has limitations because of its treatment management mode, costly monitoring, and the need for professional equipment and imagery scanning [8]. It is thus particularly urgent to explore the deeper pathogenesis of AD and develop new treatments that can prevent or slow disease progression.
Epigenetics is the bridge between the environment and heredity. Environmental changes often lead to epigenetic changes, eventually leading to disordered cellular gene expression and disease. Histone modification is a significant component of epigenetics, changing chromosome structure through acetylation, phosphorylation, methylation, and other modifications, thus affecting gene transcription and expression [9]. The advent of ultrasensitive mass spectrometry and the development of protein-modifying antibodies have facilitated the successive discovery of multiple novel histone lysine modifications, including crotonylation (Kcr) [10], lactoylation (Kla) [11], β-hydroxybutyrylation (Kbhb) [12], succinylation (Ksucc) [13], 2-hydroxyisobutyrylation (Khib) [14], and malonylation (Kmal) [15]. Over the last decade, numerous studies have explored the relationship between AD and these novel HPTMs. This review briefly summarizes the latest advances in novel HPTMs in AD, providing a fresh perspective on the development of novel targeted drugs.
Overview of previous research on HPTMs and AD
As shown in Table 1, many previous studies have investigated HPTMs and their correlation with AD, including acetylation (Kac), methylation (Kme), phosphorylation (P), and ubiquitination (Kub).
Histone acetylation, a process that promotes gene expression, is particularly important in regulating gene expression associated with learning and memory [16, 17]. Histone acetylation disorder exists in AD [18,19,20,21]. Marzi et al. quantified the genome-wide pattern of H3K27ac and revealed that H3K27ac is closely related to Aβ and tau pathology-related genes [19]. Nativio et al. found that the increase of H3K27ac and H3K9ac is associated with the transcription, chromatin and disease pathway of AD through epigenome analysis. Furthermore, they found that elevated H3K27ac and H3K9ac exacerbates amyloid-β42-driven neurodegeneration in a fly model of AD [20]. Moreover, the expression of H3K122ac and H4K16ac is downregulated in AD [20, 21]. Beyond specific histone sites, the interplay between acetylation regulatory enzymes and AD has also drawn significant attention. These enzymes affect AD neuropathology through different mechanisms, including effects on neuronal synaptic plasticity, Aβ deposition, inflammatory factors, and apoptosis [22,23,24,25,26]. Xu et al. found that the knockdown of 300/CBP reduces H3K27ac, inhibits the expression of genetic programs compensating for increased Aβ load, and leads to increased Aβ secretion [23]. Lin et al. found that the downregulation of Acyl-CoA synthetase short-chain family member 2 (ACSS2) mediates the reduction of ionotropic glutamate receptors through histone acetylation, which aggravates the damage of synaptic plasticity in AD. Conversely, ACSS2 upregulation or acetate supplementation could mitigate these deficits [22]. The modulation of acetylation may emerge as a targeted therapy to prevent or reverse the pathology and disease progression of AD.
Various molecular biology techniques were used to detect changes in methylation levels at different histone sites in the human brain and AD mouse models. Among them, H3K4me3 and H3K9me2 have been extensively studied. Elevated levels of H3K4me3 in the prefrontal cortex (PFC) and hippocampus are associated with the formation of long-term memory and the amelioration of memory deficits [27,28,29,30]. Similarly, elevated levels of H3K9me2 were detected in both mouse and human PFC regions [31]. Hypoxia may downregulate NEP (an enzyme responsible for Aβ degradation) by increasing H3K9me2 and decreasing H3 acetylation, which leads to Aβ accumulation, neurodegeneration, and AD [32]. In a study using histone methyltransferase inhibitors to treat AD mice, researchers found that histone hypermethylation can be reversed, leading to the restoration of glutamate receptor expression and excitatory synaptic function in the PFC and hippocampus [31]. Additionally, H3K4me3 and H3K9me2 are also regulated by histone methyltransferase and histone demethylase, which affect the proliferation and differentiation of neurons and the cognitive abilities of AD patients [30, 33, 34].
The phosphorylation levels of histones H3 and H4 increase in the brains of AD patients [35,36,37]. Ogawa et al. hypothesize that the increased phosphorylation of H3 in AD is confined to the cytoplasm of neurons, indicating a mitochondrial catastrophe that leads to neural dysfunctions and neurogenesis in AD [36]. Researchers have found a significant increase in γH2AX (phosphorylation of serine 139 on H2AX) in astrocytes in hippocampal and cerebral cortex regions in AD [38]. Additionally, ubiquitination of H2BK120 is heightened in the frontal cortex of AD patients [39], while H2B ubiquitination regulates histone crosstalk in learning through non-proteolytic proteome function [40]. Flamier et al. found that the Bmi1/Ring1 complex compresses developmental gene transcription via histone H2A mono-ubiquitination [41].
In summary, classical modifications occurring in different parts of the cerebral cortex and hippocampus affect memory, learning ability, neurodegeneration, and the development of AD through various pathways mediated by different factors. Despite their significance, these modifications cannot fully explain the pathogenesis of AD and facilitate the development of effective treatments, emphasizing the necessity for further research.
Summary of novel HPTMs processes
In 2007, Zhao’s team first reported two new lysine modifications, propionylation and butyrylation, initiating the discovery of a series of novel HPTMs [42]. Research into the specific regulatory mechanisms and physiopathological effects of these novel HPTMs, as well as their relationship with disease, has since expanded. Novel HPTMs have been reported to be closely associated with multiple biological processes and diseases, such as neurodegenerative diseases [43], renal diseases [44, 45], metabolic diseases [46], cardiovascular diseases [47, 48], cancer [48, 49], and HIV latency [50], thereby becoming a research focus in the epigenetics field.
Intracellular metabolites, which are substrates for ATP production and donors of HPTMs, are key to controlling gene transcription and protein translation [48]. For example, acetylCoA, derived from the glycolipid metabolic pathway, can activate acetylation modifications of histones to enable cells to handle changes in the metabolic environment [51]. Furthermore, some specific acyl-CoAs, such as butyryl-CoA and crotonyl-CoA, as well as β-hydroxybutyrylation-CoA, originate from the short-chain fatty acids generated by intestinal microbiota, providing a basis for the exogenous regulation of histone modifications affecting transcription.
Histone acylation modification involves the transfer of acyl-CoA onto histone protein amino acid residues and is tightly and dynamically regulated by multiple enzymes or non-enzymes. These novel HPTM regulatory enzymes substantially overlap with classical acetylases, including acyl-CoA synthetases, acyltransferases, and deacylases, such as ACSS2, p300/CPB, HATs, and HDACs. The association of these regulators with the disease is equally noteworthy [52]. HDACs in mammalian cells are classified into four classes: I (HDAC1, 2, 3, 8), II (HDAC4, 5, 6, 7, 9, 10), III (sirtuins 1–7), and IV (HDAC 11). Several HDACs (HDAC1, 2, 3, 6, 7, 8) and sirtuins (1, 2, 3, 6, 7) have been shown to regulate Kcr levels [53]. These regulators may become therapeutic targets and new diagnostic markers for AD. The deletion of HDAC1 and HDAC2 from mouse microglia ameliorates cognitive deficits and reduces amyloid levels by increasing amyloid phagocytosis in the microglia [54]. HDAC inhibitors have been used to treat neurodegenerative diseases due to their potential neuroprotective mechanisms through upregulating neurotrophic factors, preventing neurotoxic proteins and peptides from accumulating, and downregulating pro-inflammatory cytokines [24]. Additionally, one previous study showed that the serum concentrations of SIRT1, SIRT3, and SIRT6 were inversely related to AD [55]. A receiver operating characteristic analysis demonstrated that these serum proteins exhibit high precision in the diagnosis of AD [55]. As shown in Table 2, a more in-depth exploration of the intricate link between novel HPTMs and AD will be beneficial for identifying additional targeted biomarkers and essential therapeutic targets.
Current advances of novel HPTMs in AD
Crotonylation
Kcr, first discovered by Zhao’s team in 2011 [10], is a short-chain lysine acylation using crotonyl-CoA as the substrate, and its regulatory factors highly overlap with those of Kac [56]. Histone Kcr is particularly enriched in the transcriptional start sites (TSSs) of mammalian genomes and has a specific α, β unsaturated carbonyl structure; thus, its effect on transcription is stronger than that of histone Kac [10, 56, 57]. As a popular research topic in recent years, Kcr has been associated with various pathophysiological processes and diseases, including embryonic development [58], neurodevelopment [56], neural differentiation [59], neuron flammation [60], AD [61], neonatal hypoxic-ischemic encephalopathy [62], acute kidney injury [44], HIV [63], and even depression [43]. Recently, Kcr has been shown to modulate the expression of endocytosis-related genes, which modulate the microglia-mediated clearance of Aβ in AD [61]. Stimulating Aβ clearance is considered one of the most promising potential approaches for treating AD. Microglia play a central role in the progression of AD because of their ability to remove soluble Aβ protofibrils and protofibrillar Aβ through both endocytosis and autophagy [61, 64, 65]. Wang et al. found that nuclear paraspeckle assembly transcript 1 (NEAT1) is dysregulated in AD [61]. Mechanistically, through acylation modification histology, ChIP-seq, and other approaches, NEAT1 has been confirmed to change the acylase activity of P300 by binding to P300 and changing H3K27ac and H3K27cr, which are situated close to the TSSs of a number of gene promoters, as well as by downregulating endocytosis-related genes to inhibit Aβ uptake in AD [61]. Another study demonstrated that crocetin, the active ingredient of saffron, can exhibit neuroprotective effects in AD via the downregulation of Kcr [66]. Regrettably, due to the limited research on Kcr, there is still a lack of clarity regarding its exact regulatory role in the pathogenesis of AD, which needs to be explored in further clinical and basic studies.
Lactacylation
Lactate is a metabolite of cellular anaerobic glycolysis that is commonly considered to be a metabolic waste product with temporary energy-supplying properties. However, lactate has recently received increasing attention due to its other biological roles, including substance-energy metabolism, neurotransmitter transmission, and neurovascular coupling. In particular, the discovery of Kla has greatly broadened the biological significance of lactic acid, which exerts nonmetabolic functions; this has provided insight into the pathogenesis of several diseases. Kla, as a novel HPTM, is dynamically regulated by cellular metabolism-produced lactate, and it can directly influence the processes of gene replication, transcription, and translation, thus affecting the biological effects of cells [11]. Pan et al. discovered that Kla is a critical player in AD pathogenesis [67]. Specifically, they found that H4K12la is highly enriched in the promoter regions of microglia glycolysis-related genes and that it activates the transcription of these genes to promote microglial glycolytic activity, leading to positive feedback regulation and the intensification of microglia dysfunction in AD [67]. This study shows that metabolic disorders have an important role in neuroinflammation and the initial phases of AD, indicating novel directions for early intervention in AD [67]. Furthermore, a different study suggested that catalpol likely plays a neuroprotective role in AD by modulating Kla [68]. Consequently, Kla may emerge as a potential target for future AD therapy; however, several questions remain to be investigated, including the exact regulators and regulatory sites of lactoylation, as well as how lactoylation dynamically changes and collaborates with other types of acylation.
β-hydroxybutyrylation
β-hydroxybutyrate (BHB) is an endogenous ketone produced by metabolism. The level of BHB has been found to be decreased in patients with AD [69].
BHB can improve cognitive function and alleviate lesions in patients with AD via various mechanisms, such as modulating signaling molecules, adjusting intestinal flora, impacting Aβ and tau protein formation, enhancing mitochondrial metabolism, suppressing inflammation and lipid metabolism, and enhancing histone Kac [70]. The neuroprotective effect of BHB shows its potential as a therapeutic drug for improving cognitive function in AD patients. At present, donepezil, an acetylcholinesterase inhibitor, is used to treat AD and increases the plasma level of BHB, improving cognitive function [69]. A randomized controlled trial also confirmed that ketogenic drinks containing BHB could improve the cognitive outcomes of patients with cognitive impairment [71]. BHB is a high-energy donor of histone Kbhb, and it can bind to free CoA to form β-hydroxybutanoyl CoA [72]. Kbhb is a recently identified HPTM that is closely related to ketone metabolism. BHB is an important substrate of Kbhb, and evidence for its association with AD has been increasingly demonstrated. BHB can alleviate the pathological changes of AD and enhance cognitive function via various mechanisms; however, the therapeutic mechanism of Kbhb in AD has not been confirmed, and more research into the specific epigenetic mechanisms is required.
Succinylation
Ksucc is generated by the reaction between succinyl-CoA, a dicarboxylic acid compound metabolized from amino acid residues that is directly coupled to the tricarboxylic acid (TCA) cycle, as well as amino acid residues [13, 73]. Ksucc increases the structural moiety and charge changes to a greater extent than Kac or Kme. Accordingly, the more dramatic structural changes caused by Ksucc might induce greater alterations in protein structure and function [13]. Ksucc has a wide cellular distribution, particularly in mitochondria, and is known to regulate protease activity and gene expression [74]. Additionally, it is involved in various life processes, including glucose, amino acid, and fatty acid metabolism, as well as ketone synthesis and the scavenging of reactive oxygen species [73, 75]. The α-ketoglutarate dehydrogenase complex (KGDHC) is markedly reduced in the mitochondria of patients with AD [76]. The extensive decrease in post-translational Ksucc in the regional brain is caused by the suppression of KGDHC activity [4, 77]. Some studies have shown that KGDHC is located in the nucleus and combines with lysine acetyltransferase 2A in the promoter region of the gene to participate in the Ksucc modification of histone H3 [78]. However, the exact targets of H3 are unknown. Additionally, SIRT5, a desuccinylase, increases during AD progression [79]. It was recently confirmed that the combined effect of changes in these regulators leads to the downregulation of Ksucc in AD. A proteomic profiling study identified decreased Ksucc modification in multiple mitochondrial proteins and increased Ksucc modification of a small number of cytosolic proteins in AD [4]. Remarkably, the most significant increases took place in key APP and microtubule-associated tau sites [4]. Furthermore, studies have shown that Ksucc modification of APP contributes to Aβ accumulation and plaque formation by disrupting normal protein hydrolysis processing, while Ksucc modification of tau facilitated its aggregation into tangles and impaired microtubule assembly [4, 80]. Studies on Ksucc have primarily focused on its association with mitochondrial metabolic pathways, and the specific targets and regulators of histone Ksucc are largely unknown. Therefore, it is essential to investigate the specific roles, as well as the precise regulatory mechanisms, of histone Ksucc in AD models to meet drug development needs. In summary, Ksucc may become a potential diagnostic indicator and therapeutic target in AD.
Malonylation and 2-hydroxyisobutyrylation
Kmal and Khib were discovered by Zhao’s team in 2011 and 2014, respectively [14, 15]. Increasing research has since been conducted on these two novel acylation modifications. Du et al. used Neuro-2a cells, which can produce a mass of Aβ and consistently express N2a/APP695swe (the APP695 gene with a Swedish family mutation) to explore the role of catalpol and crocin in neuroprotection against endogenous Aβ-induced neurotoxicity [66, 68]. The crocin experiment indicated that crocin inhibited apoptosis of endogenous Aβ neurons through the mitochondrial pathway [66]. Another study showed that catalpol ameliorated neurological damage and alleviated cognitive impairment in N2a/APP695swe cells and APP/PS1 mice by modulating HPTMs, reducing apoptosis, alleviating Aβ production, and attenuating mitochondrial damage [68]. Importantly, both studies revealed changes in novel HPTMs: in crocin-treated N2a/APP695swe cells, Ksucc, Kcr, Khib, and Kmal were significantly reduced [66], while slight alterations in Kla and Khib levels were found in catalpol-treated N2a/APP695swe cells [68]. The regulation of novel HPTMs may represent a new mechanism for drug intervention to improve AD. The aforementioned findings significantly contribute to our understanding of potential novel treatment targets in AD, and provide insights for diagnostic and treatment methods aimed at HPTMs. The findings are particularly promising in the context of the challenges and prospects associated with research focused on identifying new therapeutic targets.
Conclusion and perspectives
Recent findings indicate that epigenetics and HPTMs, especially acetylation and novel acylation modifications, play a crucial role in AD pathogenesis, especially in Aβ accumulation and plaque formation. As shown in Fig. 1, we review the research on various HPTMs in AD, with a special focus on various novel modifications, to provide a fresh perspective for future exploration into the pathophysiology of AD and the development of new drugs and diagnostic methods.
Meanwhile, due to the overlap of multiple modified regulatory enzyme systems, it is particularly important to identify specific regulatory factors to prevent adverse reactions to new drugs. Acylation modification changes are dynamic and reversible. Various acylation modifications are regulated by various regulatory factors and are dynamically regulated in response to metabolic levels, such as BHB. Therefore, exogenous supplementation of modified precursor substances or the regulation of modified enzyme activity may represent a new therapeutic approach for AD.
It is worth noting that research on novel HPTMs is still relatively limited compared to that on classical HPTMs, such as acetylation and methylation. Many of these studies are limited to observing changes in the levels of HPTMs and related factors, without identifying specific action sites. In addition, some new acylation modifications (such as glutarylation and benzoylation) have not been thoroughly studied in the context of AD. The scarcity of research may be attributed to the high cost of specific antibodies and the absence of specific inhibitors for novel acylation. With the rapid development of new site-specific antibodies, acylation modification detection methods and global maps will greatly expand in the future. Although there is currently no cure for AD, drugs developed based on epigenetics and novel HPTMs are likely to effectively improve disease symptoms and prognoses in the future. Further in-depth exploration of the biological effects and regulation of novel HPTMs will broaden our perspective on the treatment of AD.
Data availability
Data will be made available upon request.
Abbreviations
- AD:
-
Alzheimer’s disease
- HPTMs:
-
Histone post-translational modifications
- Aβ:
-
Misfolded amyloid beta
- FDA:
-
The US food and drug administration
- Kcr:
-
Crotonylation
- Kla:
-
Lactoylation
- Kbhb:
-
β-Hydroxybutyrylation
- Ksucc:
-
Succinylation
- Khib:
-
2-Hydroxyisobutyrylation
- Kmal:
-
Malonylation
- Kac:
-
Acetylation
- Kme:
-
Methylation
- P:
-
Phosphorylation
- Kub:
-
Ubiquitination
- ACSS2:
-
Acetyl CoA transferase
- PFC:
-
Prefrontal cortex
- NEP:
-
An enzyme responsible for Aβ degradation
- γH2AX:
-
Phosphorylation of serine 139 on H2AX
- TSSs:
-
Transcriptional start sites
- NEAT1:
-
Nuclear paraspeckle assembly transcript 1
- BHB:
-
β-Hydroxybutyrate
- TCA:
-
Tricarboxylic acid
- KGDHC:
-
α-Ketoglutarate dehydrogenase complex
- N2a/APP695swe:
-
The APP695 gene with a Swedish family mutation
References
Hajjo R, Sabbah DA, Abusara OH, Al Bawab AQ. A review of the recent advances in Alzheimer’s disease research and the utilization of network biology approaches for prioritizing diagnostics and therapeutics. Diagnostics. 2022;12(12):2975.
Alzheimer’s disease facts and figures. Alzheimers Dement. 2022;18(4):700–89.
Nikolac Perkovic M, Videtic Paska A, Konjevod M, et al. Epigenetics of Alzheimer’s disease. Biomolecules. 2021;11(2):195.
Yang Y, Tapias V, Acosta D, et al. Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease. Nat Commun. 2022;13(1):159.
Shi Y, Holtzman DM. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat Rev Immunol. 2018;18(12):759–72.
Parums DV. Editorial: targets for disease-modifying therapies in Alzheimer’s disease, including amyloid beta and tau protein. Med Sci Monit. 2021;27: e934077.
Abyadeh M, Gupta V, Gupta V, et al. Comparative analysis of aducanumab, zagotenemab and pioglitazone as targeted treatment strategies for Alzheimer’s disease. Aging Dis. 2021;12(8):1964–76.
Huang LK, Kuan YC, Lin HW, Hu CJ. Clinical trials of new drugs for Alzheimer disease: a 2020–2023 update. J Biomed Sci. 2023;30(1):83.
Kornberg RD, Lorch Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell. 1999;98(3):285–94.
Tan M, Luo H, Lee S, et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell. 2011;146(6):1016–28.
Zhang D, Tang Z, Huang H, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574(7779):575–80.
Xie Z, Zhang D, Chung D, et al. Metabolic regulation of gene expression by histone lysine beta-hydroxybutyrylation. Mol Cell. 2016;62(2):194–206.
Zhang Z, Tan M, Xie Z, Dai L, Chen Y, Zhao Y. Identification of lysine succinylation as a new post-translational modification. Nat Chem Biol. 2011;7(1):58–63.
Dai L, Peng C, Montellier E, et al. Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark. Nat Chem Biol. 2014;10(5):365–70.
Peng C, Lu Z, Xie Z, et al. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol Cell Proteomics. 2011;10(12):012658.
Gao X, Chen Q, Yao H, et al. Epigenetics in Alzheimer’s disease. Front Aging Neurosci. 2022;14: 911635.
Peixoto L, Abel T. The role of histone acetylation in memory formation and cognitive impairments. Neuropsychopharmacology. 2013;38(1):62–76.
Schueller E, Paiva I, Blanc F, et al. Dysregulation of histone acetylation pathways in hippocampus and frontal cortex of Alzheimer’s disease patients. Eur Neuropsychopharmacol. 2020;33:101–16.
Marzi SJ, Leung SK, Ribarska T, et al. A histone acetylome-wide association study of Alzheimer’s disease identifies disease-associated H3K27ac differences in the entorhinal cortex. Nat Neurosci. 2018;21(11):1618–27.
Nativio R, Lan Y, Donahue G, et al. An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease. Nat Genet. 2020;52(10):1024–35.
Nativio R, Donahue G, Berson A, et al. Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease. Nat Neurosci. 2018;21(4):497–505.
Lin Y, Lin A, Cai L, et al. ACSS2-dependent histone acetylation improves cognition in mouse model of Alzheimer’s disease. Mol Neurodegener. 2023;18(1):47.
Xu DC, Sas-Nowosielska H, Donahue G, et al. Histone acetylation in an Alzheimer’s disease cell model promotes homeostatic amyloid-reducing pathways. Acta Neuropathol Commun. 2024;12(1):3.
Santana DA, Smith MAC, Chen ES. Histone modifications in Alzheimer’s disease. Genes. 2023;14(2):347.
Johnson AA, Sarthi J, Pirooznia SK, Reube W, Elefant F. Increasing Tip60 HAT levels rescues axonal transport defects and associated behavioral phenotypes in a Drosophila Alzheimer’s disease model. J Neurosci. 2013;33(17):7535–47.
Pirooznia SK, Sarthi J, Johnson AA, et al. Tip60 HAT activity mediates APP induced lethality and apoptotic cell death in the CNS of a Drosophila Alzheimer’s disease model. PLoS ONE. 2012;7(7): e41776.
Kerimoglu C, Agis-Balboa RC, Kranz A, et al. Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice. J Neurosci. 2013;33(8):3452–64.
Gupta S, Kim SY, Artis S, et al. Histone methylation regulates memory formation. J Neurosci. 2010;30(10):3589–99.
Kerimoglu C, Sakib MS, Jain G, et al. KMT2A and KMT2B mediate memory function by affecting distinct genomic regions. Cell Rep. 2017;20(3):538–48.
Cao Q, Wang W, Williams JB, Yang F, Wang ZJ, Yan Z. Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer’s disease. Sci Adv. 2020;6(50):8096.
Zheng Y, Liu A, Wang ZJ, et al. Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer’s disease. Brain. 2019;142(3):787–807.
Wang Z, Yang D, Zhang X, et al. Hypoxia-induced down-regulation of neprilysin by histone modification in mouse primary cortical and hippocampal neurons. PLoS ONE. 2011;6(4): e19229.
Christopher MA, Myrick DA, Barwick BG, et al. LSD1 protects against hippocampal and cortical neurodegeneration. Nat Commun. 2017;8(1):805.
Engstrom AK, Walker AC, Moudgal RA, et al. The inhibition of LSD1 via sequestration contributes to tau-mediated neurodegeneration. Proc Natl Acad Sci USA. 2020;117(46):29133–43.
Chaput D, Kirouac L, Stevens SM Jr, Padmanabhan J. Potential role of PCTAIRE-2, PCTAIRE-3 and P-Histone H4 in amyloid precursor protein-dependent Alzheimer pathology. Oncotarget. 2016;7(8):8481–97.
Ogawa O, Zhu X, Lee HG, et al. Ectopic localization of phosphorylated histone H3 in Alzheimer’s disease: a mitotic catastrophe? Acta Neuropathol. 2003;105(5):524–8.
Rao JS, Keleshian VL, Klein S, Rapoport SI. Epigenetic modifications in frontal cortex from Alzheimer’s disease and bipolar disorder patients. Transl Psychiatry. 2012;2(7): e132.
Myung NH, Zhu X, Kruman II, et al. Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes. Age. 2008;30(4):209–15.
Anderson KW, Turko IV. Histone post-translational modifications in frontal cortex from human donors with Alzheimer’s disease. Clin Proteomics. 2015;12:26.
Jarome TJ, Perez GA, Webb WM, et al. Ubiquitination of histone H2B by proteasome subunit RPT6 controls histone methylation chromatin dynamics during memory formation. Biol Psychiatry. 2021;89(12):1176–87.
Flamier A, El Hajjar J, Adjaye J, Fernandes KJ, Abdouh M, Bernier G. Modeling late-onset sporadic Alzheimer’s disease through BMI1 deficiency. Cell Rep. 2018;23(9):2653–66.
Chen Y, Sprung R, Tang Y, et al. Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol Cell Proteom. 2007;6(5):812–9.
Liu Y, Li M, Fan M, et al. Chromodomain Y-like protein-mediated histone crotonylation regulates stress-induced depressive behaviors. Biol Psychiatry. 2019;85(8):635–49.
Ruiz-Andres O, Sanchez-Nino MD, Cannata-Ortiz P, et al. Histone lysine crotonylation during acute kidney injury in mice. Dis Model Mech. 2016;9(6):633–45.
Xiang T, Zhao S, Wu Y, Li L, Fu P, Ma L. Novel post-translational modifications in the kidneys for human health and diseases. Life Sci. 2022;311(Pt B): 121188.
Li D, Zhang L, He Y, et al. Novel histone post-translational modifications in diabetes and complications of diabetes: the underlying mechanisms and implications. Biomed Pharmacother. 2022;156: 113984.
Zhou B, Xiao M, Hu H, et al. Cardioprotective role of SIRT5 in response to acute Ischemia through a novel liver-cardiac crosstalk mechanism. Front Cell Dev Biol. 2021;9: 687559.
Sun X, Zhang Y, Chen XF, Tang X. Acylations in cardiovascular biology and diseases, what’s beyond acetylation. EBioMedicine. 2023;87: 104418.
Fu Y, Yu J, Li F, Ge S. Oncometabolites drive tumorigenesis by enhancing protein acylation: from chromosomal remodelling to nonhistone modification. J Exp Clin Cancer Res. 2022;41(1):144.
Zhang H, Cai J, Li C, et al. Wogonin inhibits latent HIV-1 reactivation by downregulating histone crotonylation. Phytomedicine. 2023;116: 154855.
Kaelin WG Jr, McKnight SL. Influence of metabolism on epigenetics and disease. Cell. 2013;153(1):56–69.
Zhao S, Zhang X, Li H. Beyond histone acetylation-writing and erasing histone acylations. Curr Opin Struct Biol. 2018;53:169–77.
Li K, Wang Z. Histone crotonylation-centric gene regulation. Epigenet Chromatin. 2021;14(1):10.
Datta M, Staszewski O, Raschi E, et al. Histone deacetylases 1 and 2 regulate microglia function during development, homeostasis, and neurodegeneration in a context-dependent manner. Immunity. 2018;48(3):514–29.
Pradhan R, Singh AK, Kumar P, et al. Blood circulatory level of seven sirtuins in Alzheimer’s disease: potent biomarker based on translational research. Mol Neurobiol. 2022;59(3):1440–51.
Dai SK, Liu PP, Du HZ, et al. Histone crotonylation regulates neural stem cell fate decisions by activating bivalent promoters. EMBO Rep. 2021;22(10): e52023.
Ji Y, Sun L, Chen Y, Qin H, Xuan W. Sirtuin-derived covalent binder for the selective recognition of protein crotonylation. Angew Chem Int Ed Engl. 2022;61(31): e202205522.
Fang Y, Li X. A simple, efficient, and reliable endoderm differentiation protocol for human embryonic stem cells using crotonate. STAR Protoc. 2021;2(3): 100659.
Dai SK, Liu PP, Li X, Jiao LF, Teng ZQ, Liu CM. Dynamic profiling and functional interpretation of histone lysine crotonylation and lactylation during neural development. Development. 2022;149(14):200049.
Zou Y, Bai XH, Kong LC, et al. Involvement of histone lysine crotonylation in the regulation of nerve-injury-induced neuropathic pain. Front Immunol. 2022;13: 885685.
Wang Z, Zhao Y, Xu N, et al. NEAT1 regulates neuroglial cell mediating Abeta clearance via the epigenetic regulation of endocytosis-related genes expression. Cell Mol Life Sci. 2019;76(15):3005–18.
He X, Zhang T, Zeng Y, et al. Sodium butyrate mediates histone crotonylation and alleviated neonatal rats hypoxic-ischemic brain injury through gut-brain axis. Front Microbiol. 2022;13: 993146.
Li D, Dewey MG, Wang L, et al. Crotonylation sensitizes IAPi-induced disruption of latent HIV by enhancing p100 cleavage into p52. iScience. 2022;25(1):103649.
Mandrekar S, Jiang Q, Lee CY, Koenigsknecht-Talboo J, Holtzman DM, Landreth GE. Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J Neurosci. 2009;29(13):4252–62.
Koenigsknecht J, Landreth G. Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism. J Neurosci. 2004;24(44):9838–46.
Du J, Li Y, Song D, et al. Protective effects of crocin against endogenous Abeta-induced neurotoxicity in N2a/APP695swe cells. Psychopharmacology. 2021;238(10):2839–47.
Pan RY, He L, Zhang J, et al. Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease. Cell Metab. 2022;34(4):634–48.
Du J, Liu J, Huang X, et al. Catalpol ameliorates neurotoxicity in N2a/APP695swe cells and APP/PS1 transgenic mice. Neurotox Res. 2022;40(4):961–72.
Wan L, Lu J, Fu J, et al. Acetylcholinesterase inhibitor donepezil effects on plasma beta-hydroxybutyrate levels in the treatment of Alzheimer’s disease. Curr Alzheimer Res. 2018;15(10):917–27.
Wang JH, Guo L, Wang S, Yu NW, Guo FQ. The potential pharmacological mechanisms of beta-hydroxybutyrate for improving cognitive functions. Curr Opin Pharmacol. 2022;62:15–22.
Fortier M, Castellano CA, St-Pierre V, et al. A ketogenic drink improves cognition in mild cognitive impairment: results of a 6-month RCT. Alzheimers Dement. 2021;17(3):543–52.
Zhou T, Cheng X, He Y, et al. Function and mechanism of histone beta-hydroxybutyrylation in health and disease. Front Immunol. 2022;13:981285.
Smestad J, Erber L, Chen Y, Maher LJ. Chromatin succinylation correlates with active gene expression and is perturbed by defective TCA cycle metabolism. iScience. 2018;2:63–75.
Park J, Chen Y, Tishkoff DX, et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell. 2013;50(6):919–30.
Zhang Y, Bharathi SS, Rardin MJ, et al. Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain. J Biol Chem. 2017;292(24):10239–49.
Gibson GE, Xu H, Chen HL, Chen W, Denton TT, Zhang S. Alpha-ketoglutarate dehydrogenase complex-dependent succinylation of proteins in neurons and neuronal cell lines. J Neurochem. 2015;134(1):86–96.
Yang Y, Gibson GE. Succinylation links metabolism to protein functions. Neurochem Res. 2019;44(10):2346–59.
Wang Y, Guo YR, Liu K, et al. KAT2A coupled with the alpha-KGDH complex acts as a histone H3 succinyltransferase. Nature. 2017;552(7684):273–7.
Lutz MI, Milenkovic I, Regelsberger G, Kovacs GG. Distinct patterns of sirtuin expression during progression of Alzheimer’s disease. Neuromolecular Med. 2014;16(2):405–14.
Acosta DM, Mancinelli C, Bracken C, Eliezer D. Post-translational modifications within tau paired helical filament nucleating motifs perturb microtubule interactions and oligomer formation. J Biol Chem. 2022;298(1): 101442.
Klein HU, McCabe C, Gjoneska E, et al. Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer’s human brains. Nat Neurosci. 2019;22(1):37–46.
Hendrickx A, Pierrot N, Tasiaux B, et al. Epigenetic regulations of immediate early genes expression involved in memory formation by the amyloid precursor protein of Alzheimer disease. PLoS ONE. 2014;9(6): e99467.
Ricobaraza A, Cuadrado-Tejedor M, Perez-Mediavilla A, Frechilla D, Del Rio J, Garcia-Osta A. Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer’s disease mouse model. Neuropsychopharmacology. 2009;34(7):1721–32.
Narayan PJ, Lill C, Faull R, Curtis MA, Dragunow M. Increased acetyl and total histone levels in post-mortem Alzheimer’s disease brain. Neurobiol Dis. 2015;74:281–94.
Francis YI, Fa M, Ashraf H, et al. Dysregulation of histone acetylation in the APP/PS1 mouse model of Alzheimer’s disease. J Alzheimers Dis. 2009;18(1):131–9.
Lithner CU, Lacor PN, Zhao WQ, et al. Disruption of neocortical histone H3 homeostasis by soluble Abeta: implications for Alzheimer’s disease. Neurobiol Aging. 2013;34(9):2081–90.
Acknowledgements
We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.
Funding
This work was supported by grants from the National Natural Science Foundation of China (No. 82170834, No.81970676, and No. U22A20286); Key Research and Development Program of Science and Technology Department of Sichuan Province (No. 2022YFS0612-C2, No. 2022YFS0612, No. 2022YFS0617); the Office of Science Technology and Talent Work of Luzhou (No.2020LZXNYDP02, No. 2021LZXNYD-G01 and No. 2019LZXNYDJ40); the Project of The Health Commission of Sichuan Province (No. 19PJ294); the Project of Southwest Medical University (No. 2022QN059) and the Project of Luzhou Municipal People’s Government (2019YFS0537).
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WH and LC were responsible for the conception and design of the study. YQ, PY, WH, and DL handled data collection, analysis, and image processing. YQ, PY, WH, and DL wrote the manuscript, and LZ, JL, TZ, and JP revised it. YQ, PY, WH, and DL were responsible for the final approval of the submitted version of the manuscript. All authors contributed to the conception, writing, and editing of the manuscript, and they all read and approved the final version.
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Qin, Y., Yang, P., He, W. et al. Novel histone post-translational modifications in Alzheimer’s disease: current advances and implications. Clin Epigenet 16, 39 (2024). https://doi.org/10.1186/s13148-024-01650-w
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DOI: https://doi.org/10.1186/s13148-024-01650-w