1 5519 140 RISK FACTORS FOR ALZHEIMER'S DISEASE: ROLE OF MULTIPLE ANTIOXIDANTS, NON-STEROIDAL ANTI-INFLAMMATORY AND CHOLINERGIC AGENTS ALONE OR IN COMBINATION IN PREVENTION AND TREATMENT. THE ETIOLOGY OF ALZHEIMER'S DISEASE (AD) IS NOT WELL UNDERSTOOD. ETIOLOGIC FACTORS, CHRONIC INFLAMMATORY REACTIONS, OXIDATIVE AND NITROSYLATIVE STRESSES AND HIGH CHOLESTEROL LEVELS ARE THOUGHT TO BE IMPORTANT FOR INITIATING AND PROMOTING NEURODEGENERATIVE CHANGES COMMONLY FOUND IN AD BRAINS. EVEN IN FAMILIAL AD, OXIDATIVE STRESS PLAYS AN IMPORTANT ROLE IN THE EARLY ONSET OF THE DISEASE. MITOCHONDRIAL DAMAGE AND PROTEASOME INHIBITION REPRESENT EARLY EVENTS IN THE PATHOGENESIS OF AD, WHEREAS INCREASED PROCESSING OF AMYLOID PRECURSOR PROTEIN (APP) TO BETA-AMYLOID (ABETA) FRAGMENTS (ABETA(40) AND ABETA(42)) AND FORMATION OF SENILE PLAQUES AND NEUROFIBRILLARY TANGLES (NFTS) REPRESENT LATE EVENTS. WE PROPOSE A HYPOTHESIS THAT IN IDIOPATHIC AD, EPIGENETIC COMPONENTS OF NEURONS SUCH AS MITOCHONDRIA, PROTEASOMES AND POST-TRANSLATION PROTEIN MODIFICATIONS (PROCESSING OF AMYLOID PRECURSOR PROTEIN TO BETA-AMYLOID AND HYPERPHOSPHORYLATION OF TAU), RATHER THAN NUCLEAR GENES, ARE THE PRIMARY TARGETS FOR THE ACTION OF DIVERSE GROUPS OF NEUROTOXINS. BASED ON EPIDEMIOLOGIC, LABORATORY AND LIMITED CLINICAL STUDIES, WE PROPOSE THAT A COMBINATION OF NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) AND APPROPRIATE LEVELS AND TYPES OF MULTIPLE MICRONUTRIENTS, INCLUDING ANTIOXIDANTS, MAY BE MORE EFFECTIVE THAN THE INDIVIDUAL AGENTS IN THE PREVENTION, AND THEY, IN COMBINATION WITH A CHOLINERGIC AGENT, MAY BE MORE EFFECTIVE IN THE TREATMENT OF AD THAN THE INDIVIDUAL AGENTS ALONE. IN ADDITION, AGENTS, WHICH CAN PREVENT FORMATION OF PLAQUES OR DISSOLVE THESE PLAQUES MAY FURTHER ENHANCE THE EFFICACY OF OUR PROPOSED TREATMENT STRATEGY. 2002 2 5766 45 SPECIAL ISSUE: ALZHEIMER'S DISEASE. MORE THAN 45 MILLION PEOPLE WORLDWIDE HAVE ALZHEIMER'S DISEASE (AD), A DETERIORATION OF MEMORY AND OTHER COGNITIVE DOMAINS THAT LEADS TO DEATH WITHIN 3 TO 9 YEARS AFTER DIAGNOSIS. THE PRINCIPAL RISK FACTOR FOR AD IS AGE. AS THE AGING POPULATION INCREASES, THE PREVALENCE WILL APPROACH 131 MILLION CASES WORLDWIDE IN 2050. AD IS THEREFORE A GLOBAL PROBLEM CREATING A RAPIDLY GROWING EPIDEMIC AND BECOMING A MAJOR THREAT TO HEALTHCARE IN OUR SOCIETIES. IT HAS BEEN MORE THAN 20 YEARS SINCE IT WAS FIRST PROPOSED THAT THE NEURODEGENERATION IN AD MAY BE CAUSED BY DEPOSITION OF AMYLOID-BETA (ABETA) PEPTIDES IN PLAQUES IN BRAIN TISSUE. ACCORDING TO THE AMYLOID HYPOTHESIS, ACCUMULATION OF ABETA PEPTIDES, RESULTING FROM A CHRONIC IMBALANCE BETWEEN ABETA PRODUCTION AND ABETA CLEARANCE IN THE BRAIN, IS THE PRIMARY INFLUENCE DRIVING AD PATHOGENESIS. CURRENT AVAILABLE MEDICATIONS APPEAR TO BE ABLE TO PRODUCE MODERATE SYMPTOMATIC BENEFITS BUT NOT TO STOP DISEASE PROGRESSION. THE SEARCH FOR BIOMARKERS AS WELL AS NOVEL THERAPEUTIC APPROACHES FOR AD HAS BEEN A MAJOR FOCUS OF RESEARCH. RECENT FINDINGS, HOWEVER, SHOW THAT NEURONAL-INJURY BIOMARKERS ARE INDEPENDENT OF ABETA SUGGESTING EPIGENETIC MODIFICATIONS, GENE-GENE AND/OR GENE-ENVIRONMENT INTERACTIONS IN THE DISEASE ETIOLOGY, AND CALLING FOR RECONSIDERATION OF THE PATHOLOGICAL CASCADE AND ASSESSMENT OF ALTERNATIVE THERAPEUTIC STRATEGIES. IN ADDITION, RECENT RESEARCH RESULTS REGARDING THE EXPRESSION OF THE BETA-AMYLOID PRECURSOR PROTEIN (APP) GENE RESULTING IN THE PRESENCE OF VARIOUS APP-MRNA ISOFORMS AND THEIR QUANTIFICATION, ESPECIALLY FOR IDENTIFYING THE MOST ABUNDANT ONE THAT MAY DECISIVE FOR THE NORMAL STATUS OR DISEASE RISK, HAVE BEEN REPORTED. AS SUCH, A MORE COMPLETE UNDERSTANDING OF AD PATHOGENESIS WILL LIKELY REQUIRE GREATER INSIGHTS INTO THE PHYSIOLOGICAL FUNCTION OF THE BETA-AMYLOID PRECURSOR PROTEIN (APP). 2018 3 5598 42 ROLES OF NON-CODING RNA IN ALZHEIMER'S DISEASE PATHOPHYSIOLOGY. ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISORDER THAT IS ACCOMPANIED BY DEFICITS IN MEMORY AND COGNITIVE FUNCTIONS. THE DISEASE IS PATHOLOGICALLY CHARACTERISED BY THE ACCUMULATION AND AGGREGATION OF AN EXTRACELLULAR PEPTIDE REFERRED TO AS AMYLOID-BETA (ABETA) IN THE FORM OF AMYLOID PLAQUES AND THE INTRACELLULAR AGGREGATION OF A HYPERPHOSPHORELATED PROTEIN TAU IN THE FORM OF NEUROFIBRILLARY TANGLES (NFTS) THAT CAUSE NEUROINFLAMMATION, SYNAPTIC DYSFUNCTION, AND OXIDATIVE STRESS. THE SEARCH FOR PATHOMECHANISMS LEADING TO DISEASE ONSET AND PROGRESSION HAS IDENTIFIED MANY KEY PLAYERS THAT INCLUDE GENETIC, EPIGENETIC, BEHAVIOURAL, AND ENVIRONMENTAL FACTORS, WHICH LEND SUPPORT TO THE FACT THAT THIS IS A MULTI-FACETED DISEASE WHERE FAILURE IN VARIOUS SYSTEMS CONTRIBUTES TO DISEASE ONSET AND PROGRESSION. ALTHOUGH THE VAST MAJORITY OF INDIVIDUALS PRESENT WITH THE SPORADIC (NON-GENETIC) FORM OF THE DISEASE, DYSFUNCTIONS IN NUMEROUS PROTEIN-CODING AND NON-CODING GENES HAVE BEEN IMPLICATED IN MECHANISMS CONTRIBUTING TO THE DISEASE. RECENT STUDIES HAVE PROVIDED STRONG EVIDENCE FOR THE ASSOCIATION OF NON-CODING RNAS (NCRNAS) WITH AD. IN THIS REVIEW, WE HIGHLIGHT THE CURRENT FINDINGS ON CHANGES OBSERVED IN CIRCULAR RNA (CIRCRNA), MICRORNA (MIRNA), SHORT INTERFERING RNA (SIRNA), PIWI-INTERACTING RNA (PIRNA), AND LONG NON-CODING RNA (LNCRNA) IN AD. VARIATIONS IN THESE NCRNAS COULD POTENTIALLY SERVE AS BIOMARKERS OR THERAPEUTIC TARGETS FOR THE DIAGNOSIS AND TREATMENT OF ALZHEIMER'S DISEASE. WE ALSO DISCUSS THE RESULTS OF STUDIES THAT HAVE TARGETED THESE NCRNAS IN CELLULAR AND ANIMAL MODELS OF AD WITH A VIEW FOR TRANSLATING THESE FINDINGS INTO THERAPIES FOR ALZHEIMER'S DISEASE. 2023 4 2227 28 EPIGENETIC MODIFICATIONS OF CHRONIC HYPOXIA-MEDIATED NEURODEGENERATION IN ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS THE MOST COMMON NEURODEGENERATIVE DISORDER AFFECTING THE ELDERLY PEOPLE. AD IS CHARACTERIZED BY PROGRESSIVE AND GRADUAL DECLINE IN COGNITIVE FUNCTION AND MEMORY LOSS. WHILE FAMILIAL EARLY-ONSET AD IS USUALLY ASSOCIATED WITH GENE MUTATIONS, THE ETIOLOGY OF SPORADIC LATE-ONSET FORM OF AD IS LARGELY UNKNOWN. IT HAS BEEN REPORTED THAT ENVIRONMENTAL FACTORS AND EPIGENETIC ALTERATIONS SIGNIFICANTLY CONTRIBUTE TO THE PROCESS OF AD. OUR PREVIOUS STUDIES HAVE DOCUMENTED THAT CHRONIC HYPOXIA IS ONE OF THE ENVIRONMENTAL FACTORS THAT MAY TRIGGER THE AD DEVELOPMENT AND AGGRAVATE THE DISEASE PROGRESSION. IN THIS REVIEW, WE WILL SUMMARIZE THE PATHOLOGICAL EFFECTS OF CHRONIC HYPOXIA ON THE ONSET AND DEVELOPMENT OF AD AND PUT FORWARD THE POSSIBLE MOLECULE MECHANISMS UNDERLYING THE CHRONIC HYPOXIA MEDIATED AD PATHOGENESIS. FINALLY, WE PROPOSE THAT EPIGENETIC REGULATIONS MAY REPRESENT NEW OPPORTUNITY FOR THE THERAPEUTIC INTERVENTION OF THIS DISEASE. 2014 5 4682 38 NEW PATHWAYS IDENTIFY NOVEL DRUG TARGETS FOR THE PREVENTION AND TREATMENT OF ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS AN INCURABLE, PROGRESSIVE NEURODEGENERATIVE DISORDER. AD IS A COMPLEX AND MULTIFACTORIAL DISEASE THAT IS RESPONSIBLE FOR 60-80% OF DEMENTIA CASES. AGING, GENETIC FACTORS, AND EPIGENETIC CHANGES ARE THE MAIN RISK FACTORS FOR AD. TWO AGGREGATION-PRONE PROTEINS PLAY A DECISIVE ROLE IN AD PATHOGENESIS: BETA-AMYLOID (ABETA) AND HYPERPHOSPHORYLATED TAU (PTAU). BOTH OF THEM FORM DEPOSITS AND DIFFUSIBLE TOXIC AGGREGATES IN THE BRAIN. THESE PROTEINS ARE THE BIOMARKERS OF AD. DIFFERENT HYPOTHESES HAVE TRIED TO EXPLAIN AD PATHOGENESIS AND SERVED AS PLATFORMS FOR AD DRUG RESEARCH. EXPERIMENTS DEMONSTRATED THAT BOTH ABETA AND PTAU MIGHT START NEURODEGENERATIVE PROCESSES AND ARE NECESSARY FOR COGNITIVE DECLINE. THE TWO PATHOLOGIES ACT IN SYNERGY. INHIBITION OF THE FORMATION OF TOXIC ABETA AND PTAU AGGREGATES HAS BEEN AN OLD DRUG TARGET. RECENTLY, SUCCESSFUL ABETA CLEARANCE BY MONOCLONAL ANTIBODIES HAS RAISED NEW HOPES FOR AD TREATMENTS IF THE DISEASE IS DETECTED AT EARLY STAGES. MORE RECENTLY, NOVEL TARGETS, E.G., IMPROVEMENTS IN AMYLOID CLEARANCE FROM THE BRAIN, APPLICATION OF SMALL HEAT SHOCK PROTEINS (HSPS), MODULATION OF CHRONIC NEUROINFLAMMATION BY DIFFERENT RECEPTOR LIGANDS, MODULATION OF MICROGLIAL PHAGOCYTOSIS, AND INCREASE IN MYELINATION HAVE BEEN REVEALED IN AD RESEARCH. 2023 6 6061 30 THE DEVELOPMENT PROSPECTION OF HDAC INHIBITORS AS A POTENTIAL THERAPEUTIC DIRECTION IN ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISEASE, WHICH IS ASSOCIATED WITH LEARNING AND MEMORY IMPAIRMENT IN THE ELDERLY. RECENT STUDIES HAVE FOUND THAT TREATING AD IN THE WAY OF CHROMATIN REMODELING VIA HISTONE ACETYLATION IS A PROMISING THERAPEUTIC REGIMEN. IN A NUMBER OF RECENT STUDIES, INHIBITORS OF HISTONE DEACETYLASE (HDACS) HAVE BEEN FOUND TO BE A NOVEL PROMISING THERAPEUTIC AGENTS FOR NEUROLOGICAL DISORDERS, PARTICULARLY FOR AD AND OTHER NEURODEGENERATIVE DISEASES. ALTHOUGH HDAC INHIBITORS HAVE THE ABILITY TO AMELIORATE COGNITIVE IMPAIRMENT, SUCCESSFUL TREATMENTS IN THE CLASSIC AD ANIMAL MODEL ARE RARELY TRANSLATED INTO CLINICAL TRIALS. AS FOR THE REDUCTION OF UNWANTED SIDE EFFECTS, THE DEVELOPMENT OF HDAC INHIBITORS WITH INCREASED ISOFORM SELECTIVITY OR SEEKING OTHER DIRECTIONS IS A KEY ISSUE THAT NEEDS TO BE ADDRESSED. THE REVIEW FOCUSED ON LITERATURES ON EPIGENETIC MECHANISMS IN RECENT YEARS, ESPECIALLY ON HISTONE ACETYLATION IN TERMS OF THE ENHANCEMENT OF SPECIFICITY, EFFICACY AND AVOIDING SIDE EFFECTS FOR TREATING AD. 2017 7 5580 46 ROLE OF NEUROTOXICANTS IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE: A MECHANISTIC INSIGHT. ALZHEIMER'S DISEASE (AD) IS THE MOST CONSPICUOUS CHRONIC NEURODEGENERATIVE SYNDROME, WHICH HAS BECOME A SIGNIFICANT CHALLENGE FOR THE GLOBAL HEALTHCARE SYSTEM. MULTIPLE STUDIES HAVE CORROBORATED A CLEAR ASSOCIATION OF NEUROTOXICANTS WITH AD PATHOGENICITY, SUCH AS AMYLOID BETA (ABETA) PROTEINS AND NEUROFIBRILLARY TANGLES (NFTS), SIGNALLING PATHWAY MODIFICATIONS, CELLULAR STRESS, COGNITIVE DYSFUNCTIONS, NEURONAL APOPTOSIS, NEUROINFLAMMATION, EPIGENETIC MODIFICATION, AND SO ON. THIS REVIEW, THEREFORE, AIMED TO ADDRESS SEVERAL ESSENTIAL MECHANISMS AND SIGNALLING CASCADES, INCLUDING WNT (WINGLESS AND INT.) SIGNALLING PATHWAY, AUTOPHAGY, MAMMALIAN TARGET OF RAPAMYCIN (MTOR), PROTEIN KINASE C (PKC) SIGNALLING CASCADES, CELLULAR REDOX STATUS, ENERGY METABOLISM, GLUTAMATERGIC NEUROTRANSMISSIONS, IMMUNE CELL STIMULATIONS (E.G. MICROGLIA, ASTROCYTES) AS WELL AS AN AMYLOID PRECURSOR PROTEIN (APP), PRESENILIN-1 (PSEN1), PRESENILIN-2 (PSEN2) AND OTHER AD-RELATED GENE EXPRESSIONS THAT HAVE BEEN PRETENTIOUS AND MODULATED BY THE VARIOUS NEUROTOXICANTS. THIS REVIEW CONCLUDED THAT NEUROTOXICANTS PLAY A MOMENTOUS ROLE IN DEVELOPING AD THROUGH MODULATING VARIOUS SIGNALLING CASCADES. NEVERTHELESS, COMPREHENSION OF THIS RISK AGENT-INDUCED NEUROTOXICITY IS FAR TOO LITTLE. MORE IN-DEPTH EPIDEMIOLOGICAL AND SYSTEMATIC INVESTIGATIONS ARE NEEDED TO UNDERSTAND THE POTENTIAL MECHANISMS BETTER TO ADDRESS THESE NEUROTOXICANTS AND IMPROVE APPROACHES TO THEIR RISK EXPOSURE THAT AID IN AD PATHOGENESIS.KEY MESSAGESINEVITABLE CASCADE MECHANISMS OF HOW ALZHEIMER'S DISEASE-RELATED (AD-RELATED) GENE EXPRESSIONS ARE MODULATED BY NEUROTOXICANTS HAVE BEEN DISCUSSED.INVOLVEMENT OF THE NEUROTOXICANTS-INDUCED PATHWAYS CAUSED AN EXTENDED RISK OF AD IS EXPLICITED.INTEGRATION OF CELL CULTURE, ANIMALS AND POPULATION-BASED ANALYSIS ON THE CLINICAL SEVERITY OF AD IS ADDRESSED. 2021 8 6701 39 VASCULAR FACTORS AND EPIGENETIC MODIFICATIONS IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS A DEBILITATING ILLNESS WITH NO KNOWN CURE. NOWADAYS ACCUMULATING EVIDENCE SUGGESTED THAT THE VASCULAR ENDOTHELIUM AND CHRONIC HYPOPERFUSION MAY PLAY IMPORTANT ROLE IN PATHOBIOLOGY OF AD. THE VASCULAR ENDOTHELIUM WHICH REGULATES THE PASSAGE OF MACROMOLECULES AND CIRCULATING CELLS FROM BLOOD TO TISSUE, IS A MAJOR TARGET OF OXIDATIVE STRESS, PLAYING A CRITICAL ROLE IN THE PATHOPHYSIOLOGY OF VASCULAR DISEASES. SINCE THE VASCULAR ENDOTHELIUM, NEURONS AND GLIA ARE ALL ABLE TO SYNTHESIZE, STORE AND RELEASE REACTIVE OXYGEN SPECIES (ROS) AND VASCULAR ACTIVE SUBSTANCES IN RESPONSE TO CERTAIN STIMULI, THEIR CONTRIBUTION TO THE PATHOPHYSIOLOGY OF AD CAN BE VERY IMPORTANT. NEW EVIDENCE INDICATES THAT CONTINUOUS FORMATION OF FREE ROS INDUCES CELLULAR DAMAGE AND DECREASES ANTIOXIDANT DEFENSES. SPECIFICALLY, OXIDATIVE STRESS INCREASES VASCULAR ENDOTHELIAL PERMEABILITY AND PROMOTES LEUKOCYTE ADHESION. WE SUMMARIZE THE REPORTS THAT SPORADIC, LATE-ONSET OF AD RESULTS FROM VASCULAR ETIOLOGY. RECENTLY AN INVOLVEMENT OF EPIGENETIC ALTERATIONS IN THE ETIOLOGY OF AD IS ALSO INTENSIVELY INVESTIGATED. GAINING A MORE COMPLETE UNDERSTANDING OF THE ESSENTIAL COMPONENTS AND UNDERLYING MECHANISMS INVOLVED IN EPIGENETIC REGULATION COULD LEAD TO NOVEL TREATMENTS FOR A NUMBER OF NEUROLOGICAL AND PSYCHIATRIC CONDITIONS. 2012 9 676 32 BRAIN AGING: A IANUS-FACED PLAYER BETWEEN HEALTH AND NEURODEGENERATION. NEURODEGENERATIVE DISEASES ARE INCURABLE DEBILITATING DISORDERS CHARACTERIZED BY STRUCTURAL AND FUNCTIONAL NEURONAL LOSS. APPROXIMATELY 30 MILLION PEOPLE ARE AFFECTED WORLDWIDE, AND THIS NUMBER IS PREDICTED TO REACH MORE THAN 150 MILLION BY 2050. NEURODEGENERATIVE DISORDERS INCLUDE ALZHEIMER'S, PARKINSON'S, AND PRION DISEASES AMONG OTHERS. THESE DISORDERS ARE CHARACTERIZED BY THE ACCUMULATION OF AGGREGATING PROTEINS FORMING AMYLOID, RESPONSIBLE FOR THE DISEASE-ASSOCIATED PATHOLOGICAL LESIONS. THE AGGREGATION OF AMYLOIDOGENIC PROTEINS CAN RESULT EITHER IN GAINING OF TOXIC FUNCTIONS, DERIVED FROM THE DAMAGE PROVOKED BY THESE DEPOSITS IN AFFECTED TISSUE, OR IN A LOSS OF FUNCTIONS, DUE TO THE SEQUESTRATION AND THE CONSEQUENT INABILITY OF THE AGGREGATING PROTEIN TO ENSURE ITS PHYSIOLOGICAL ROLE. WHILE IT IS WIDELY ACCEPTED THAT AGING REPRESENTS THE MAIN RISK FACTOR FOR NEURODEGENERATION, THERE IS STILL NO CLEAR CUT-OFF LINE BETWEEN THE TWO CONDITIONS. INDEED, MANY OF THE PATHWAYS THAT ARE COMMONLY ALTERED IN NEURODEGENERATION-MISFOLDED PROTEIN ACCUMULATION, CHRONIC INFLAMMATION, MITOCHONDRIAL DYSFUNCTION, IMPAIRED IRON HOMEOSTASIS, EPIGENETIC MODIFICATIONS-HAVE BEEN OFTEN CORRELATED ALSO WITH HEALTHY AGING. THIS OVERLAP COULD BE EXPLAINED BY THE FACT THAT THE CONTINUOUS ACCUMULATION OF CELLULAR DAMAGES, TOGETHER WITH A PROGRESSIVE DECLINE IN METABOLIC EFFICIENCY DURING AGING, MAKES THE NEURONS MORE VULNERABLE TO TOXIC INJURIES. WHEN A GIVEN THRESHOLD IS EXCEEDED, ALL THESE ALTERATIONS MIGHT GIVE RISE TO PATHOLOGICAL PHENOTYPES THAT ULTIMATELY LEAD TO NEURODEGENERATION. 2020 10 6347 26 THE ROLE OF EPIGENETICS IN NEUROINFLAMMATORY-DRIVEN DISEASES. NEURODEGENERATIVE DISORDERS ARE CHARACTERIZED BY THE PROGRESSIVE LOSS OF CENTRAL AND/OR PERIPHERAL NERVOUS SYSTEM NEURONS. WITHIN THIS CONTEXT, NEUROINFLAMMATION COMES UP AS ONE OF THE MAIN FACTORS LINKED TO NEURODEGENERATION PROGRESSION. IN FACT, NEUROINFLAMMATION HAS BEEN RECOGNIZED AS AN OUTSTANDING FACTOR FOR ALZHEIMER'S DISEASE (AD), AMYOTROPHIC LATERAL SCLEROSIS (ALS), PARKINSON'S DISEASE (PD), AND MULTIPLE SCLEROSIS (MS). INTERESTINGLY, NEUROINFLAMMATORY DISEASES ARE CHARACTERIZED BY DRAMATIC CHANGES IN THE EPIGENETIC PROFILE, WHICH MIGHT PROVIDE NOVEL PROGNOSTIC AND THERAPEUTIC FACTORS TOWARDS NEUROINFLAMMATORY TREATMENT. DEEP CHANGES IN DNA AND HISTONE METHYLATION, ALONG WITH HISTONE ACETYLATION AND ALTERED NON-CODING RNA EXPRESSION, HAVE BEEN REPORTED AT THE ONSET OF INFLAMMATORY DISEASES. THE AIM OF THIS WORK IS TO REVIEW THE CURRENT KNOWLEDGE ON THIS FIELD. 2022 11 4635 48 NEUROINFLAMMATORY MECHANISMS IN PARKINSON'S DISEASE: POTENTIAL ENVIRONMENTAL TRIGGERS, PATHWAYS, AND TARGETS FOR EARLY THERAPEUTIC INTERVENTION. MOST ACUTE AND CHRONIC NEURODEGENERATIVE CONDITIONS ARE ACCOMPANIED BY NEUROINFLAMMATION; YET THE EXACT NATURE OF THE INFLAMMATORY PROCESSES AND WHETHER THEY MODIFY DISEASE PROGRESSION IS NOT WELL UNDERSTOOD. IN THIS REVIEW, WE DISCUSS THE KEY EPIDEMIOLOGICAL, CLINICAL, AND EXPERIMENTAL EVIDENCE IMPLICATING INFLAMMATORY PROCESSES IN THE PROGRESSIVE DEGENERATION OF THE DOPAMINERGIC (DA) NIGROSTRIATAL PATHWAY AND THEIR POTENTIAL CONTRIBUTION TO THE PATHOPHYSIOLOGY OF PARKINSON'S DISEASE (PD). GIVEN THAT INTERPLAY BETWEEN GENETICS AND ENVIRONMENT ARE LIKELY TO CONTRIBUTE TO RISK FOR DEVELOPMENT OF IDIOPATHIC PD, RECENT DATA SHOWING INTERACTIONS BETWEEN PRODUCTS OF GENES LINKED TO HERITABLE PD THAT FUNCTION TO PROTECT DA NEURONS AGAINST OXIDATIVE OR PROTEOLYTIC STRESS AND INFLAMMATION PATHWAYS WILL BE DISCUSSED. CELLULAR MECHANISMS ACTIVATED OR ENHANCED BY INFLAMMATORY PROCESSES THAT MAY CONTRIBUTE TO MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, OR APOPTOSIS OF DOPAMINERGIC (DA) NEURONS WILL BE REVIEWED, WITH SPECIAL EMPHASIS ON TUMOR NECROSIS FACTOR (TNF) AND INTERLEUKIN-1-BETA (IL-1BETA) SIGNALING PATHWAYS. EPIGENETIC FACTORS WHICH HAVE THE POTENTIAL TO TRIGGER NEUROINFLAMMATION, INCLUDING ENVIRONMENTAL EXPOSURES AND AGE-ASSOCIATED CHRONIC INFLAMMATORY CONDITIONS, WILL BE DISCUSSED AS POSSIBLE 'SECOND-HIT' TRIGGERS THAT MAY AFFECT DISEASE ONSET OR PROGRESSION OF IDIOPATHIC PD. IF INFLAMMATORY PROCESSES HAVE AN ACTIVE ROLE IN NIGROSTRIATAL PATHWAY DEGENERATION, THEN EVIDENCE SHOULD EXIST TO INDICATE THAT SUCH PROCESSES BEGIN IN THE EARLY STAGES OF DISEASE AND THAT THEY CONTRIBUTE TO NEURONAL DYSFUNCTION AND/OR HASTEN NEURODEGENERATION OF THE NIGROSTRIATAL PATHWAY. THERAPEUTICALLY, IF ANTI-INFLAMMATORY INTERVENTIONS CAN BE SHOWN TO RESCUE NIGRAL DA NEURONS FROM DEGENERATION AND LOWER PD RISK, THEN TIMELY USE OF ANTI-INFLAMMATORY THERAPIES SHOULD BE INVESTIGATED FURTHER IN WELL-DESIGNED CLINICAL TRIALS FOR THEIR ABILITY TO PREVENT OR DELAY THE PROGRESSIVE LOSS OF NIGRAL DA NEURONS IN GENETICALLY SUSCEPTIBLE POPULATIONS. 2007 12 2447 32 EPIGENETIC STUDIES IN ALZHEIMER'S DISEASE: CURRENT FINDINGS, CAVEATS, AND CONSIDERATIONS FOR FUTURE STUDIES. ALZHEIMER'S DISEASE (AD) IS A SPORADIC, CHRONIC NEURODEGENERATIVE DISEASE, USUALLY OCCURRING LATE IN LIFE. THE LAST DECADE HAS WITNESSED TREMENDOUS ADVANCES IN OUR UNDERSTANDING ABOUT THE GENETIC BASIS OF AD, BUT A LARGE AMOUNT OF THE VARIANCE IN DISEASE RISK REMAINS TO BE EXPLAINED. EPIGENETIC MECHANISMS, WHICH DEVELOPMENTALLY REGULATE GENE EXPRESSION VIA MODIFICATIONS TO DNA, HISTONE PROTEINS, AND CHROMATIN, HAVE BEEN HYPOTHESIZED TO PLAY A ROLE IN OTHER COMPLEX NEUROBIOLOGICAL DISEASES, AND STUDIES TO IDENTIFY GENOME-WIDE EPIGENETIC CHANGES IN AD ARE CURRENTLY UNDER WAY. HOWEVER, THE SIMPLE BRUTE-FORCE APPROACH THAT HAS BEEN SUCCESSFULLY EMPLOYED IN GENOME-WIDE ASSOCIATION STUDIES IS UNLIKELY TO BE SUCCESSFUL IN EPIGENOME-WIDE ASSOCIATION STUDIES OF NEURODEGENERATION. A MORE ACADEMIC APPROACH TO UNDERSTANDING THE ROLE OF EPIGENETIC VARIATION IN AD IS REQUIRED, WITH CAREFUL CONSIDERATION OF STUDY DESIGN, METHODOLOGICAL APPROACHES, TISSUE-SPECIFICITY, AND CAUSAL INFERENCE. IN THIS ARTICLE, WE REVIEW THE EMPIRICAL LITERATURE SUPPORTING A ROLE FOR EPIGENETIC PROCESSES IN AD, AND DISCUSS IMPORTANT CONSIDERATIONS AND FUTURE DIRECTIONS FOR THIS NEW AND EMERGING FIELD OF RESEARCH. 2013 13 1459 41 DISORDERED APP METABOLISM AND NEUROVASCULATURE IN TRAUMA AND AGING: COMBINED RISKS FOR CHRONIC NEURODEGENERATIVE DISORDERS. TRAUMATIC BRAIN INJURY (TBI), ADVANCED AGE, AND CEREBRAL VASCULAR DISEASE ARE FACTORS CONFERRING INCREASED RISK FOR LATE ONSET ALZHEIMER'S DISEASE (AD). THESE CONDITIONS ARE ALSO RELATED PATHOLOGICALLY THROUGH MULTIPLE INTERACTING MECHANISMS. THE HALLMARK PATHOLOGY OF AD CONSISTS OF PATHOLOGICAL AGGREGATES OF AMYLOID-BETA (ABETA) PEPTIDES AND TAU PROTEINS. THESE MOLECULES ARE ALSO INVOLVED IN NEUROPATHOLOGY OF SEVERAL OTHER CHRONIC NEURODEGENERATIVE DISEASES, AND ARE UNDER INTENSE INVESTIGATION IN THE AFTERMATH OF TBI AS POTENTIAL CONTRIBUTORS TO THE RISK FOR DEVELOPING AD AND CHRONIC TRAUMATIC ENCEPHALOPATHY (CTE). THE PATHOLOGY OF TBI IS COMPLEX AND DEPENDENT ON INJURY SEVERITY, AGE-AT-INJURY, AND LENGTH OF TIME BETWEEN INJURY AND NEUROPATHOLOGICAL EVALUATION. IN ADDITION, THE MECHANISMS INFLUENCING PATHOLOGY AND RECOVERY AFTER TBI LIKELY INVOLVE GENETIC/EPIGENETIC FACTORS AS WELL AS ADDITIONAL DISORDERS OR COMORBID STATES RELATED TO AGE AND CENTRAL AND PERIPHERAL VASCULAR HEALTH. IN THIS REGARD, DYSFUNCTION OF THE AGING NEUROVASCULAR SYSTEM COULD BE AN IMPORTANT LINK BETWEEN TBI AND CHRONIC NEURODEGENERATIVE DISEASES, EITHER AS A PRECIPITATING EVENT OR RELATED TO ACCUMULATION OF AD-LIKE PATHOLOGY WHICH IS AMPLIFIED IN THE CONTEXT OF AGING. THUS WITH ADVANCED AGE AND VASCULAR DYSFUNCTION, TBI CAN TRIGGER SELF-PROPAGATING CYCLES OF NEURONAL INJURY, PATHOLOGICAL PROTEIN AGGREGATION, AND SYNAPTIC LOSS RESULTING IN CHRONIC NEURODEGENERATIVE DISEASE. IN THIS REVIEW WE DISCUSS EVIDENCE SUPPORTING TBI AND AGING AS DUAL, INTERACTING RISK FACTORS FOR AD, AND THE ROLE OF ABETA AND CEREBRAL VASCULAR DYSFUNCTION IN THIS RELATIONSHIP. EVIDENCE IS DISCUSSED THAT ABETA IS INVOLVED IN CYTO- AND SYNAPTO-TOXICITY AFTER SEVERE TBI, AND THAT ITS CHRONIC EFFECTS ARE POTENTIATED BY AGING AND IMPAIRED CEREBRAL VASCULAR FUNCTION. FROM A THERAPEUTIC PERSPECTIVE, WE EMPHASIZE THAT IN THE FIELDS OF TBI- AND AGING-RELATED NEURODEGENERATION PROTECTIVE STRATEGIES SHOULD INCLUDE PRESERVATION OF NEUROVASCULAR FUNCTION. 2017 14 4646 32 NEUROPATHOLOGICAL MECHANISMS ASSOCIATED WITH PESTICIDES IN ALZHEIMER'S DISEASE. ENVIRONMENTAL TOXICANTS HAVE BEEN IMPLICATED IN NEURODEGENERATIVE DISEASES, AND PESTICIDE EXPOSURE IS A SUSPECTED ENVIRONMENTAL RISK FACTOR FOR ALZHEIMER'S DISEASE (AD). SEVERAL EPIDEMIOLOGICAL ANALYSES HAVE AFFIRMED A LINK BETWEEN PESTICIDES AND INCIDENCE OF SPORADIC AD. MEANWHILE, IN VITRO AND ANIMAL MODELS OF AD HAVE SHED LIGHT ON POTENTIAL NEUROPATHOLOGICAL MECHANISMS. IN THIS PAPER, A PERSPECTIVE ON NEUROPATHOLOGICAL MECHANISMS UNDERLYING PESTICIDES' INDUCTION OF AD IS PROVIDED. PROPOSED MECHANISMS RANGE FROM GENERIC OXIDATIVE STRESS INDUCTION IN NEURONS TO MORE AD-SPECIFIC PROCESSES INVOLVING AMYLOID-BETA (ABETA) AND HYPERPHOSPHORYLATED TAU (P-TAU). MECHANISMS THAT ARE MORE SPECULATIVE OR INDIRECT IN NATURE, INCLUDING SOMATIC MUTATION, EPIGENETIC MODULATION, IMPAIRMENT OF ADULT NEUROGENESIS, AND MICROBIOTA DYSBIOSIS, ARE ALSO DISCUSSED. CHRONIC TOXICITY MECHANISMS OF ENVIRONMENTAL PESTICIDE EXPOSURE CROSSTALKS IN COMPLEX WAYS AND COULD POTENTIALLY BE MUTUALLY ENHANCING, THUS MAKING THE DECIPHERING OF SIMPLISTIC CAUSAL RELATIONSHIPS DIFFICULT. 2020 15 2010 41 EPIGENETIC BASIS OF LEAD-INDUCED NEUROLOGICAL DISORDERS. ENVIRONMENTAL LEAD (PB) EXPOSURE IS CLOSELY ASSOCIATED WITH PATHOGENESIS OF A RANGE OF NEUROLOGICAL DISORDERS, INCLUDING ALZHEIMER'S DISEASE (AD), PARKINSON'S DISEASE (PD), AMYOTROPHIC LATERAL SCLEROSIS (ALS), ATTENTION DEFICIT/HYPERACTIVITY DISORDER (ADHD), ETC. EPIGENETIC MACHINERY MODULATES NEURAL DEVELOPMENT AND ACTIVITIES, WHILE FAULTY EPIGENETIC REGULATION CONTRIBUTES TO THE DIVERSE FORMS OF CNS (CENTRAL NERVOUS SYSTEM) ABNORMALITIES AND DISEASES. AS A POTENT EPIGENETIC MODIFIER, LEAD IS THOUGHT TO CAUSE NEUROLOGICAL DISORDERS THROUGH MODULATING EPIGENETIC MECHANISMS. SPECIFICALLY, INCREASING EVIDENCE LINKED ABERRANT DNA METHYLATIONS, HISTONE MODIFICATIONS AS WELL AS NCRNAS (NON-CODING RNAS) WITH AD CASES, AMONG WHICH CIRCRNA (CIRCULAR RNA) STANDS OUT AS A NEW AND PROMISING FIELD FOR ASSOCIATION STUDIES. IN 23-YEAR-OLD PRIMATES WITH DEVELOPMENTAL LEAD TREATMENT, ZAWIA GROUP DISCOVERED A VARIETY OF EPIGENETIC CHANGES RELATING TO AD PATHOGENESIS. THIS IS A DIRECT EVIDENCE IMPLICATING EPIGENETIC BASIS IN LEAD-INDUCED AD ANIMALS WITH AN ENTIRE LIFESPAN. ADDITIONALLY, SOME EPIGENETIC MOLECULES ASSOCIATED WITH AD ETIOLOGY WERE ALSO KNOWN TO RESPOND TO CHRONIC LEAD EXPOSURE IN COMPARABLE DISEASE MODELS, INDICATING POTENTIALLY INTERLACED MECHANISMS WITH RESPECT TO THE STUDIED NEUROTOXIC AND PATHOLOGICAL EVENTS. OF NOTE, EPIGENETIC MOLECULES ACTED VIA GLOBALLY OR SELECTIVELY INFLUENCING THE EXPRESSION OF DISEASE-RELATED GENES. COMPARED TO AD, THE ASSOCIATION OF LEAD EXPOSURE WITH OTHER NEUROLOGICAL DISORDERS WERE PRIMARILY SUPPORTED BY EPIDEMIOLOGICAL SURVEY, WITH FEWER REPORTS CONNECTING EPIGENETIC REGULATORS WITH LEAD-INDUCED PATHOGENESIS. SOME PHARMACEUTICALS, SUCH AS HDAC (HISTONE DEACETYLASE) INHIBITORS AND DNA METHYLATION INHIBITORS, WERE DEVELOPED TO DEAL WITH CNS DISEASE BY TARGETING EPIGENETIC COMPONENTS. STILL, UNDERSTANDINGS ARE INSUFFICIENT REGARDING THE CAUSE-CONSEQUENCE RELATIONS OF EPIGENETIC FACTORS AND NEUROLOGICAL ILLNESS. THEREFORE, CLEAR EVIDENCE SHOULD BE PROVIDED IN FUTURE INVESTIGATIONS TO ADDRESS DETAILED ROLES OF NOVEL EPIGENETIC FACTORS IN LEAD-INDUCED NEUROLOGICAL DISORDERS, AND EFFORTS OF DEVELOPING SPECIFIC EPIGENETIC THERAPEUTICS SHOULD BE APPRAISED. 2020 16 1199 30 CORTICOTROPIN RELEASING FACTOR-BINDING PROTEIN (CRF-BP) AS A POTENTIAL NEW THERAPEUTIC TARGET IN ALZHEIMER'S DISEASE AND STRESS DISORDERS. ALZHEIMER'S DISEASE IS THE MOST COMMON CAUSE OF DEMENTIA AND ONE OF THE MOST COMPLEX HUMAN NEURODEGENERATIVE DISEASES. NUMEROUS STUDIES HAVE DEMONSTRATED A CRITICAL ROLE OF THE ENVIRONMENT IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF THE DISEASE, WHERE DAILY LIFE STRESS PLAYS AN IMPORTANT ROLE. A LOT OF EPIGENETIC STUDIES HAVE LED TO THE CONCLUSION THAT CHRONIC STRESS AND STRESS-RELATED DISORDERS PLAY AN IMPORTANT PART IN THE ONSET OF NEURODEGENERATIVE DISORDERS, AND AN ENORMOUS AMOUNT OF RESEARCH YIELDED VALUABLE DISCOVERIES BUT HAS SO FAR NOT LED TO THE DEVELOPMENT OF EFFECTIVE TREATMENT STRATEGIES FOR ALZHEIMER'S DISEASE. CORTICOTROPIN-RELEASING FACTOR (CRF) IS ONE OF THE MAJOR HORMONES AND AT THE SAME TIME A NEUROPEPTIDE ACTING IN STRESS RESPONSE. DEREGULATION OF PROTEIN LEVELS OF CRF IS INVOLVED IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE, BUT LITTLE IS KNOWN ABOUT THE PRECISE ROLES OF CRF AND ITS BINDING PROTEIN, CRF-BP, IN NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE SUMMARIZE THE KEY EVIDENCE FOR AND AGAINST THE INVOLVEMENT OF STRESS-ASSOCIATED MODULATION OF THE CRF SYSTEM IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE AND DISCUSS HOW RECENT FINDINGS COULD LEAD TO NEW POTENTIAL TREATMENT POSSIBILITIES IN ALZHEIMER'S DISEASE BY USING CRF-BP AS A THERAPEUTIC TARGET. 2019 17 4783 31 NUTRIGENOMICS IN PARKINSON'S DISEASE: DIVERSITY OF MODULATORY ACTIONS OF POLYPHENOLS ON EPIGENETIC EFFECTS INDUCED BY TOXINS. ALTHOUGH THE PATHOGENESIS OF PARKINSON'S DISEASE (PD) IS NOT COMPLETELY UNDERSTOOD, THERE IS A CONSENSUS THAT IT CAN BE CAUSED BY MULTIFACTORIAL MECHANISMS INVOLVING GENETIC SUSCEPTIBILITY, EPIGENETIC MODIFICATIONS INDUCED BY TOXINS AND MITOCHONDRIAL DYSFUNCTION. IN THE PAST 20 YEARS, GREAT EFFORTS HAVE BEEN MADE IN ORDER TO CLARIFY MOLECULAR MECHANISMS THAT ARE RISK FACTORS FOR THIS DISEASE, AS WELL AS TO IDENTIFY BIOACTIVE AGENTS FOR PREVENTION AND SLOWING DOWN OF ITS PROGRESSION. NUTRACEUTICAL PRODUCTS HAVE RECEIVED SUBSTANTIAL INTEREST DUE TO THEIR NUTRITIONAL, SAFE AND THERAPEUTIC EFFECTS ON SEVERAL CHRONIC DISEASES. THE AIM OF THIS REVIEW WAS TO GATHER THE MAIN EVIDENCE OF THE EPIGENETIC MECHANISMS INVOLVED IN THE NEUROPROTECTIVE EFFECTS OF PHENOLIC COMPOUNDS CURRENTLY UNDER INVESTIGATION FOR THE TREATMENT OF TOXIN-INDUCED PD. THESE STUDIES CONFIRM THAT THE NEUROPROTECTIVE ACTIONS OF POLYPHENOLS INVOLVE COMPLEX EPIGENETIC MODULATIONS, DEMONSTRATING THAT THE INTAKE OF THESE NATURAL COMPOUNDS CAN BE A PROMISING, LOW-COST, PHARMACOGENOMIC STRATEGY AGAINST THE DEVELOPMENT OF PD. 2023 18 554 38 AUTOPHAGY IN HUMAN HEALTH AND DISEASE: NOVEL THERAPEUTIC OPPORTUNITIES. SIGNIFICANCE: IN EUKARYOTES, AUTOPHAGY REPRESENTS A HIGHLY EVOLUTIONARY CONSERVED PROCESS, THROUGH WHICH MACROMOLECULES AND CYTOPLASMIC MATERIAL ARE DEGRADED INTO LYSOSOMES AND RECYCLED FOR BIOSYNTHETIC OR ENERGETIC PURPOSES. DYSFUNCTION OF THE AUTOPHAGIC PROCESS HAS BEEN ASSOCIATED WITH THE ONSET AND DEVELOPMENT OF MANY HUMAN CHRONIC PATHOLOGIES, SUCH AS CARDIOVASCULAR, METABOLIC, AND NEURODEGENERATIVE DISEASES AS WELL AS CANCER. RECENT ADVANCES: CURRENTLY, COMPREHENSIVE RESEARCH IS BEING CARRIED OUT TO DISCOVER NEW THERAPEUTIC AGENTS THAT ARE ABLE TO MODULATE THE AUTOPHAGIC PROCESS IN VIVO. RECENT EVIDENCE HAS SHOWN THAT A LARGE NUMBER OF NATURAL BIOACTIVE COMPOUNDS ARE INVOLVED IN THE REGULATION OF AUTOPHAGY BY MODULATING SEVERAL TRANSCRIPTIONAL FACTORS AND SIGNALING PATHWAYS. CRITICAL ISSUES: CRITICAL ISSUES THAT DESERVE PARTICULAR ATTENTION ARE THE INADEQUATE UNDERSTANDING OF THE COMPLEX ROLE OF AUTOPHAGY IN DISEASE PATHOGENESIS, THE LIMITED AVAILABILITY OF THERAPEUTIC DRUGS, AND THE LACK OF CLINICAL TRIALS. IN THIS CONTEXT, THE EFFECTS THAT NATURAL BIOACTIVE COMPOUNDS EXERT ON AUTOPHAGIC MODULATION SHOULD BE CLEARLY HIGHLIGHTED, SINCE THEY DEPEND ON THE TYPE AND STAGE OF THE PATHOLOGICAL CONDITIONS OF DISEASES. FUTURE DIRECTIONS: RESEARCH EFFORTS SHOULD NOW FOCUS ON UNDERSTANDING THE SURVIVAL-SUPPORTING AND DEATH-PROMOTING ROLES OF AUTOPHAGY, HOW NATURAL COMPOUNDS INTERACT EXACTLY WITH THE AUTOPHAGIC TARGETS SO AS TO INDUCE OR INHIBIT AUTOPHAGY AND ON THE EVALUATION OF THEIR PHARMACOLOGICAL EFFECTS IN A MORE IN-DEPTH AND MECHANISTIC WAY. IN ADDITION, CLINICAL STUDIES ON AUTOPHAGY-INDUCING NATURAL PRODUCTS ARE STRONGLY ENCOURAGED, ALSO TO HIGHLIGHT SOME FUNDAMENTAL ASPECTS, SUCH AS THE DOSE, THE DURATION, AND THE POSSIBLE SYNERGISTIC ACTION OF THESE COMPOUNDS WITH CONVENTIONAL THERAPY. 2019 19 5811 31 STRESS - (SELF) EATING: EPIGENETIC REGULATION OF AUTOPHAGY IN RESPONSE TO PSYCHOLOGICAL STRESS. AUTOPHAGY IS A CONSTITUTIVE AND CYTOPROTECTIVE CATABOLIC PROCESS. ABERRATIONS IN AUTOPHAGY LEAD TO A MULTITUDE OF DEGENERATIVE DISORDERS, WITH NEURODEGENERATION BEING ONE OF THE MOST WIDELY STUDIED AUTOPHAGY-RELATED DISORDERS. WHILE THE FIELD HAS LARGELY BEEN FOCUSING ON THE CYTOSOLIC CONSTITUENTS AND PROCESSES OF AUTOPHAGY, RECENT STUDIES ARE INCREASINGLY APPRECIATING THE ROLE OF CHROMATIN MODIFICATIONS AND EPIGENETIC REGULATION IN AUTOPHAGY MAINTENANCE. AUTOPHAGY HAS BEEN IMPLICATED IN THE REGULATION OF NEUROGENESIS, AND DISRUPTION OF NEUROGENESIS IN RESPONSE TO PSYCHOLOGICAL STRESS IS A PROXIMAL RISK FACTOR FOR DEVELOPMENT OF NEUROPSYCHIATRIC DISORDERS SUCH AS MAJOR DEPRESSIVE DISORDER (MDD). IN THIS REVIEW, WE WILL DISCUSS THE REGULATION OF AUTOPHAGY IN NORMAL NEUROGENESIS AS WELL AS DURING CHRONIC PSYCHOLOGICAL STRESS, FOCUSING ON THE EPIGENETIC CONTROL OF AUTOPHAGY IN THESE CONTEXTS, AND ALSO HIGHLIGHT THE LACUNAE IN OUR UNDERSTANDING OF THIS PROCESS. THE SYSTEMATIC STUDY OF THESE REGULATORY MECHANISMS WILL PROVIDE A NOVEL THERAPEUTIC STRATEGY, BASED ON THE USE EPIGENETIC REGULATORS OF AUTOPHAGY TO ENHANCE NEUROGENESIS AND POTENTIALLY ALLEVIATE STRESS-RELATED BEHAVIORAL DISORDERS. 2019 20 2350 40 EPIGENETIC REGULATION OF NEUROINFLAMMATION IN PARKINSON'S DISEASE. NEUROINFLAMMATION IS ONE OF THE MOST SIGNIFICANT FACTORS INVOLVED IN THE INITIATION AND PROGRESSION OF PARKINSON'S DISEASE. PD IS A NEURODEGENERATIVE DISORDER WITH A MOTOR DISABILITY LINKED WITH VARIOUS COMPLEX AND DIVERSIFIED RISK FACTORS. THESE FACTORS TRIGGER MYRIADS OF CELLULAR AND MOLECULAR PROCESSES, SUCH AS MISFOLDING DEFECTIVE PROTEINS, OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, AND NEUROTOXIC SUBSTANCES THAT INDUCE SELECTIVE NEURODEGENERATION OF DOPAMINE NEURONS. THIS NEURONAL DAMAGE ACTIVATES THE NEURONAL IMMUNE SYSTEM, INCLUDING GLIAL CELLS AND INFLAMMATORY CYTOKINES, TO TRIGGER NEUROINFLAMMATION. THE TRANSITION OF ACUTE TO CHRONIC NEUROINFLAMMATION ENHANCES THE SUSCEPTIBILITY OF INFLAMMATION-INDUCED DOPAMINERGIC NEURON DAMAGE, FORMING A VICIOUS CYCLE AND PROMPTING AN INDIVIDUAL TO PD DEVELOPMENT. EPIGENETIC MECHANISMS RECENTLY HAVE BEEN AT THE FOREFRONT OF THE REGULATION OF NEUROINFLAMMATORY FACTORS IN PD, PROPOSING A NEW DAWN FOR BREAKING THIS VICIOUS CYCLE. THIS REVIEW EXAMINED THE CORE EPIGENETIC MECHANISMS INVOLVED IN THE ACTIVATION AND PHENOTYPIC TRANSFORMATION OF GLIAL CELLS MEDIATED NEUROINFLAMMATION IN PD. WE FOUND THAT EPIGENETIC MECHANISMS DO NOT WORK INDEPENDENTLY, DESPITE BEING COORDINATED WITH EACH OTHER TO ACTIVATE NEUROINFLAMMATORY PATHWAYS. IN THIS REGARD, WE ATTEMPTED TO FIND THE SYNERGIC CORRELATION AND CONTRIBUTION OF THESE EPIGENETIC MODIFICATIONS WITH VARIOUS NEUROINFLAMMATORY PATHWAYS TO BROADEN THE CANVAS OF UNDERLYING PATHOLOGICAL MECHANISMS INVOLVED IN PD DEVELOPMENT. MOREOVER, THIS STUDY HIGHLIGHTED THE DUAL CHARACTERISTICS (NEUROPROTECTIVE/NEUROTOXIC) OF THESE EPIGENETIC MARKS, WHICH MAY COUNTERACT PD PATHOGENESIS AND MAKE THEM POTENTIAL CANDIDATES FOR DEVISING FUTURE PD DIAGNOSIS AND TREATMENT. 2021