The pathogenesis of Alzheimer's disease involves β amyloid (Aβ) accumulation known to induce synaptic dysfunction and neurodegeneration. The brain's vulnerability to oxidative stress (OS) is considered a crucial detrimental factor in Alzheimer's disease. OS and Aβ are linked to each other because Aβ induces OS, and OS increases the Aβ deposition. Thus, the answer to the question "which comes first: the chicken or the egg?" remains extremely difficult. In any case, the evidence for the primary occurrence of oxidative stress in AD is attractive. Thus, evidence indicates that a long period of gradual oxidative damage accumulation precedes and results in the appearance of clinical and pathological AD symptoms, including Aβ deposition, neurofibrillary tangle formation, metabolic dysfunction, and cognitive decline. Moreover, oxidative stress plays a crucial role in the pathogenesis of many risk factors for AD. Alzheimer's disease begins many years before its symptoms, and antioxidant treatment can be an important therapeutic target for attacking the disease.

Oxidative Stress and Beta Amyloid in Alzheimer's Disease. Which Comes First: The Chicken or the Egg?

Background 
Suicide is a common phenomenon affecting people of all ages. There is a strong relationship between suicidal ideation and depressive disorders. Increasing number of studies suggest that epigenetic modifications in certain brain areas are the main mechanism through which environmental and genetic factors interact with each other contributing to the development of mental disorders. To verify this hypothesis, some epigenetic marks: H3K9/14ac, HDAC2/3, H3K27me2 and Sin3a, as well as p-S421-MeCP2/MeCP2 were examined. On the other hand, BDNF protein level were studied.


Materials and methods 
Western blot analysis were performed in the frontal cortex (FCx) and hippocampus (HP) of suicide victims (n = 14) and non-suicidal controls (n = 8). The differences between groups and correlations between selected proteins were evaluated using Mann-Whitney U-test and Spearman’s rank correlation.


Results 
Statistically significant decrease in H3K9/14ac (FCx:↓~23%;HP:↓~33%) combined with increase in HDAC3 (FCx:↑~103%;HP:↑~85% in HP) protein levels in suicides compared to the controls was shown. These alterations were accompanied by an increase in H3K27me2 (FCx:↑45%;HP:↑~59%) and Sin3a (HP:↑50%) levels and decrease in p-S421-MeCP2/MeCP2 protein ratio (HP:↓~55%;FCx:↓~27%). Moreover, reduced BDNF protein level (FCx:↓~43%;HP:↓~28%) in suicides was observed. On the other hand, some significant correlations (e.g. between H3K9/14ac and HDAC2 or between BDNF and p-S421-MeCP2/MeCP2) were demonstrated.


Conclusions 
Our findings confirm the role of epigenetic component and BDNF protein in suicidal behavior. Lowered BDNF protein level in suicides is probably due to decrease in histone acetylation and increased level of factors related with deacetylation and methylation processes, including MeCP2 factor, which may operate bidirectionally (an activator or inhibitor of transcription).

/pdf/epigenetic-marks-and-their-relationship-with-bdnf-in-the-2it82l1krt.pdf

Epigenetic marks and their relationship with BDNF in the brain of suicide victims

Clozapine is an atypical antipsychotic used in treatment-resistant bipolar disorder. There is evidence for its anti-suicidal, anti-aggressive properties and efficacy in substance use comorbidities. Despite guidelines, the drug is used in 1.5% of bipolar patients only. Considering its effectiveness in treatment-resistant cases as well as its epigenetic effects it may become transformative treatment in bipolar disorder impacting the clinical course and psychosocial burden of the disease.

/pdf/clozapine-as-transformative-treatment-in-bipolar-patients-4o0bivaxml.pdf

Clozapine As Transformative Treatment In Bipolar Patients.

According to the World Health Organization (WHO), more than 700,000 people die per year due to suicide. Suicide risk factors include a previous suicide attempt and psychiatric disorders. The highest mortality rate in suicide worldwide is due to depression. Current evidence suggests that suicide etiopathogenesis is associated with neuroinflammation that activates the kynurenine pathway and causes subsequent serotonin depletion and stimulation of glutamate neurotransmission. These changes are accompanied by decreased BDNF (brain-derived neurotrophic factor) levels in the brain, which is often linked to impaired neuroplasticity and cognitive deficits. Most suicidal patients have a hyperactive hypothalamus–pituitary–adrenal (HPA) axis. Epigenetic mechanisms control the above-mentioned neurobiological changes associated with suicidal behaviour. Suicide risk could be attenuated by appropriate psychological treatment, electroconvulsive treatment, and drugs: lithium, ketamine, esketamine, clozapine. In this review, we present the etiopathogenesis of suicide behaviour and explore the mechanisms of action of anti-suicidal treatments, pinpointing similarities among them.

Neurobiological Basis of Increased Risk for Suicidal Behaviour

\n Background: 5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification that is highly abundant in nervous system. It has been reported that 5hmC is significant associated with Alzheimer’s disease (AD). Changes in 5hmC signatures can be detected in circulating cell-free DNA (cfDNA), which has shown potential as a non-invasive liquid biopsy material. However, there is no research about genome-wide profiling of 5hmC in cfDNA and its potential for the diagnosis of AD to date. Methods: We carried out a case-control study and used a highly sensitive and selective high-throughput sequencing of chemical labels to detect the genome-wide profiles of 5hmC in human cfDNA and identified differentially hydroxymethylated regions (DhMRs) in AD patients and the control. Results: We detected a significant difference of 5hmC enrichment in gene bodies which were linked to multiple AD pathogenesis-associated signaling pathways in AD patients compared with cognitively normal controls. AD patients can be well distinguished from cognitively normal controls by differentially hydroxymethylated regions (DhMRs) in cfDNA. Specially, we found 7 distinct genes (RABEP1, CPNE4, DNAJC15, REEP3, ROR1, CAMK1D, and RBFOX1) had prediction diagnostic potential based on their significant correlations with MMSE and MoCA scores. Conclusions: The present results suggest that 5hmC markers derived from plasma cfDNA can be served as an effective, minimally invasive biomarkers for clinical auxiliary diagnosis of late-onset AD. Trial registration: Chinese Clinical Trial Registry, ChiCTR2100042537, registered 13 January 2021-retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=120582.

5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Diagnostic Biomarkers for Late-Onset Alzheimer’s Disease

There are currently no validated biomarkers which can be used to accurately diagnose Alzheimer's disease (AD) or to distinguish it from other dementia-causing neuropathologies Moreover, to date, only symptomatic treatments exist for this progressive neurodegenerative disorder In the search for new, more reliable biomarkers and potential therapeutic options, epigenetic modifications have emerged as important players in the pathogenesis of AD The aim of the article was to provide a brief overview of the current knowledge regarding the role of epigenetics (including mitoepigenetics) in AD, and the possibility of applying these advances for future AD therapy Extensive research has suggested an important role of DNA methylation and hydroxymethylation, histone posttranslational modifications, and non-coding RNA regulation (with the emphasis on microRNAs) in the course and development of AD Recent studies also indicated mitochondrial DNA (mtDNA) as an interesting biomarker of AD, since dysfunctions in the mitochondria and lower mtDNA copy number have been associated with AD pathophysiology The current evidence suggests that epigenetic changes can be successfully detected, not only in the central nervous system, but also in the cerebrospinal fluid and on the periphery, contributing further to their potential as both biomarkers and therapeutic targets in AD

Epigenetics of Alzheimer's Disease.

Genome-wide DNA methylation in suicide victims revealing impact on gene expression.

Background: Given that approximately 70% of miRNAs in the body are neuronal, we critically assessed current studies on miRNAs and suicidal behavior. Materials & Methods: To further define the role of miRNAs in suicide, we searched for studies on extracellular vesicles (exosomes) because miRNAs are particularly enriched in exosomes. miRNAs also have important physiological roles, and they can cross the blood-brain barrier and participate in cell-to-cell communication with both nearby and distant cells. Results & Conclusion: This critical assessment suggests that several miRNAs can be closely related to neurophysiology, suicidal behavior, and psychiatric disorders. However, clear overlap is poor due to either different methodologies applied or to molecular differences between suicidal behaviors and studied psychiatric disorders.

Biomarkers for suicidal behavior: miRNAs and their potential for diagnostics through liquid biopsy - a systematic review.

Abstract Objectives Epigenetic mechanisms are involved in regulation of many pathologies, including suicidal behaviour. However, the factors through which epigenetics affect suicidal behaviour are not fully understood. Methods We analysed DNA methylation of eight neuropsychiatric genes (NR3C1, SLC6A4, HTR1A, TPH2, SKA2, MAOA, GABRA1, and NRIP3) in brain regions (hippocampus, insula, amygdala, Brodmann area 46) and blood of 25 male suicide victims and 28 male control subjects, using bisulphite next-generation sequencing. Results Comparing mean methylation values, notable changes were observed in NR3C1 (insula p-value = 0.05), HTR1A (insula p-value < 0.001, blood p-value = 0.001), SKA2 (insula p-value = 0.03, blood p-value = 0.016), MAOA (blood p-value < 0.001), GABRA1 (insula p-value = 0.05, blood p-value = 0.024) and NRIP3 (hippocampus p-value = 0.001, insula p-value = 0.002, amygdala p-value = 0.014). Comparing methylation pattern between blood and brain, similarity was observed between blood and insula for HTR1A. Gene expression analysis in hippocampus revealed changes in expression of NR3C1 (p-value = 0.049), SLC6A4 (p-value = 0.017) and HTR1A (p-value = 0.053). Conclusions Results provide an insight into the altered state of DNA methylation in suicidal behaviour. Epigenetic differences could therefore affect suicidal behaviour in both previously known and in novel neuropsychiatric candidate genes.

Targeted sequencing approach: Comprehensive analysis of DNA methylation and gene expression across blood and brain regions in suicide victims

Depressive disorder is a complex, heterogeneous disease that affects approximately 280 million people worldwide. Environmental, genetic, and neurobiological factors contribute to the depressive state. Since the nervous system is susceptible to shifts in activity of epigenetic modifiers, these allow for significant plasticity and response to rapid changes in the environment. Among the most studied epigenetic modifications in depressive disorder is DNA methylation, with findings centered on the brain-derived neurotrophic factor gene, the glucocorticoid receptor gene, and the serotonin transporter gene. In order to identify biomarkers that would be useful in clinical settings, for diagnosis and for treatment response, further research on antidepressants and alterations they cause in the epigenetic landscape throughout the genome is needed. Studies on cornerstone antidepressants, such as selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, norepinephrine, and dopamine reuptake inhibitors and their effects on depressive disorder are available, but systematic conclusions on their effects are still hard to draw due to the highly heterogeneous nature of the studies. In addition, two novel drugs, ketamine and esketamine, are being investigated particularly in association with treatment of resistant depression, which is one of the hot topics of contemporary research and the field of precision psychiatry.

Katarina Kouter

Papers

Epigenetics of Alzheimer's Disease.

Genome-wide DNA methylation in suicide victims revealing impact on gene expression.

Biomarkers for suicidal behavior: miRNAs and their potential for diagnostics through liquid biopsy - a systematic review.

Targeted sequencing approach: Comprehensive analysis of DNA methylation and gene expression across blood and brain regions in suicide victims

Depressive disorder and antidepressants from an epigenetic point of view