1 4682 119 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 2 5519 38 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 3 5580 38 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 4 1459 31 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 5 6893 27 [SLEEP AND DEMENTIA]. AGING IS ASSOCIATED WITH CHANGES IN SLEEP STRUCTURE AND CEREBRAL DEPOSITION OF AMYLOID BETA AND TAU PROTEINS. SLEEP DISTURBANCES PRECEDE THE ONSET OF DEMENTIA BY YEARS. COMORBID SLEEP DISORDERS, SUCH AS INSOMNIA AND SLEEP-DISORDERED BREATHING, A FAMILY HISTORY OF DEMENTIA AND EPIGENETIC FACTORS CAN CONTRIBUTE TO THE DEVELOPMENT OF DEMENTIA. THIS ARTICLE EXPLORES THE QUESTION OF THE INTERACTION BETWEEN SLEEP AND DEMENTIA BASED ON THE EXISTING LITERATURE. ALTERATIONS CAUSED BY SLOW WAVE SLEEP LEAD TO CHANGES IN THE GLYMPHATIC CLEARANCE OF AMYLOID BETA, TAU PROTEINS AND OTHER PROTEINS. TRANSIENT AND CHRONIC SLEEP DISORDERS CAUSE DISTURBANCES IN THE BRAIN AREAS RESPONSIBLE FOR COGNITION AND BEHAVIOR. SLEEP-REGULATING BRAIN AREAS ARE THE FIRST TO BE AFFECTED IN THE NEURODEGENERATIVE PROCESS AND ACCELERATE THE RISK OF DEMENTIA. CIRCADIAN AGE-RELATED CHANGES IN AMYLOID BETA AND TAU PROTEINS AFFECT THE AMOUNT AND DEPTH OF SLEEP AND VICE VERSA. AMYLOID BETA IN CEREBROSPINAL FLUID SHOWS AN INVERSE CORRELATION WITH SLEEP. OREXINS MODULATE AMYLOID BETA AND SLEEP. 2023 6 4646 27 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 7 6367 30 THE ROLE OF MICROGLIA IN THE ETIOLOGY AND EVOLUTION OF CHRONIC TRAUMATIC ENCEPHALOPATHY. CHRONIC TRAUMATIC ENCEPHALOPATHY (CTE) IS A PROGRESSIVE NEURODEGENERATIVE DISEASE THAT PRESENTS AS A LATE SEQUELA FROM TRAUMATIC BRAIN INJURY (TBI). TBI IS A GROWING AND UNDER-RECOGNIZED PUBLIC HEALTH CONCERN WITH A HIGH DEGREE OF MORBIDITY AND LARGE ASSOCIATED GLOBAL COSTS. WHILE THE IMMUNE RESPONSE TO TBI IS COMPLEX, ITS CONTRIBUTION TO THE DEVELOPMENT OF CTE REMAINS LARGELY UNKNOWN. IN THIS REVIEW, WE SUMMARIZE THE CURRENT UNDERSTANDING OF THE LINK BETWEEN CTE AND THE RESIDENT INNATE IMMUNE SYSTEM OF THE BRAIN-MICROGLIA. WE DISCUSS THE NEUROPATHOLOGY UNDERLYING CTE INCLUDING THE CREATION AND AGGREGATION OF PHOSPHORYLATED TAU PROTEIN INTO NEUROFIBRILLARY TANGLES AND THE FORMATION OF AMYLOID BETA DEPOSITS. WE ALSO PRESENT HOW MICROGLIA, THE RESIDENT INNATE IMMUNE CELLS OF THE BRAIN, DRIVE THE CONTINUOUS LOW-LEVEL INFLAMMATION ASSOCIATED WITH THE INSIDIOUS ONSET OF CTE. IN THIS REVIEW, WE CONCLUDE THAT THE LATENCY PERIOD BETWEEN THE INDEX BRAIN INJURY AND THE LONG-TERM DEVELOPMENT OF CTE PRESENTS AN OPPORTUNITY FOR THERAPEUTIC INTERVENTION. ENCOURAGING ADVANCES WITH MICROTUBULE STABILIZERS, CIS P-TAU ANTIBODIES, AND THE ABILITY TO THERAPEUTICALLY ALTER THE INFLAMMATORY STATE OF MICROGLIA HAVE SHOWN POSITIVE RESULTS IN BOTH ANIMAL AND HUMAN TRIALS. LOOKING FORWARD, RECENT ADVANCEMENTS IN NEXT-GENERATION SEQUENCING TECHNOLOGY FOR THE STUDY OF GENOMIC, TRANSCRIPTOMIC, AND EPIGENETIC INFORMATION WILL PROVIDE AN OPPORTUNITY FOR SIGNIFICANT ADVANCEMENT IN OUR UNDERSTANDING OF PROREPAIR AND PRO-INJURY GENE SIGNATURES ALLOWING FOR TARGETED INTERVENTION IN THIS HIGHLY MORBID INJURY PROCESS. 2017 8 5766 41 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 9 4638 31 NEURON-SPECIFIC METHYLOME ANALYSIS REVEALS EPIGENETIC REGULATION AND TAU-RELATED DYSFUNCTION OF BRCA1 IN ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISEASE CHARACTERIZED BY PATHOLOGY OF ACCUMULATED AMYLOID BETA (ABETA) AND PHOSPHORYLATED TAU PROTEINS IN THE BRAIN. POSTMORTEM DEGRADATION AND CELLULAR COMPLEXITY WITHIN THE BRAIN HAVE LIMITED APPROACHES TO MOLECULARLY DEFINE THE CAUSAL RELATIONSHIP BETWEEN PATHOLOGICAL FEATURES AND NEURONAL DYSFUNCTION IN AD. TO OVERCOME THESE LIMITATIONS, WE ANALYZED THE NEURON-SPECIFIC DNA METHYLOME OF POSTMORTEM BRAIN SAMPLES FROM AD PATIENTS, WHICH ALLOWED DIFFERENTIALLY HYPOMETHYLATED REGION OF THE BRCA1 PROMOTER TO BE IDENTIFIED. EXPRESSION OF BRCA1 WAS SIGNIFICANTLY UP-REGULATED IN AD BRAINS, CONSISTENT WITH ITS HYPOMETHYLATION. BRCA1 PROTEIN LEVELS WERE ALSO ELEVATED IN RESPONSE TO DNA DAMAGE INDUCED BY ABETA. BRCA1 BECAME MISLOCALIZED TO THE CYTOPLASM AND HIGHLY INSOLUBLE IN A TAU-DEPENDENT MANNER, RESULTING IN DNA FRAGMENTATION IN BOTH IN VITRO CELLULAR AND IN VIVO MOUSE MODELS. BRCA1 DYSFUNCTION UNDER ABETA BURDEN IS CONSISTENT WITH CONCOMITANT DETERIORATION OF GENOMIC INTEGRITY AND SYNAPTIC PLASTICITY. THE BRCA1 PROMOTER REGION OF AD MODEL MICE BRAIN WAS SIMILARLY HYPOMETHYLATED, INDICATING AN EPIGENETIC MECHANISM UNDERLYING BRCA1 REGULATION IN AD. OUR RESULTS SUGGEST DETERIORATION OF DNA INTEGRITY AS A CENTRAL CONTRIBUTING FACTOR IN AD PATHOGENESIS. MOREOVER, THESE DATA DEMONSTRATE THE TECHNICAL FEASIBILITY OF USING NEURON-SPECIFIC DNA METHYLOME ANALYSIS TO FACILITATE DISCOVERY OF ETIOLOGICAL CANDIDATES IN SPORADIC NEURODEGENERATIVE DISEASES. 2017 10 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 11 1344 24 DETECTION OF BRAIN AMYLOID BETA DEPOSITION IN PATIENTS WITH NEUROPSYCHOLOGICAL IMPAIRMENT AFTER TRAUMATIC BRAIN INJURY: PET EVALUATION USING PITTSBURGH COMPOUND-B. OBJECTIVE: TRAUMATIC BRAIN INJURY (TBI) IS AN EPIGENETIC RISK FACTOR FOR ALZHEIMER'S DISEASE (AD) AND AMYLOID BETA (ABETA) DEPOSITION IS OBSERVED HISTOPATHOLOGICALLY IN THE TRAUMATIZED BRAIN. THIS STUDY WAS CONDUCTED TO DETECT CEREBRAL ABETA DEPOSITION USING AMYLOID POSITRON EMISSION TOMOGRAPHY (PET) IN PATIENTS WITH NEUROPSYCHOLOGICAL IMPAIRMENT AFTER TBI. METHODS: TWELVE PATIENTS WITH POST-TRAUMATIC NEUROPSYCHOLOGICAL IMPAIRMENT (11 MEN AND ONE WOMAN, AGE RANGE = 21-78 YEARS) WERE EXAMINED USING PITTSBURGH COMPOUND B ((11)C-PIB) PET AT THE CHRONIC STAGE AFTER TBI (RANGE = 5-129 MONTHS). RESULTS: (11)C-PIB WAS POSITIVE IN THREE PATIENTS AND NEGATIVE IN THE OTHER NINE PATIENTS. THERE WAS NO CORRELATION BETWEEN (11)C-PIB DEPOSITION AND THE SEVERITY OF INJURY; INITIAL CT FINDINGS; ELAPSED TIME FROM THE INJURY; AND NEUROPSYCHOLOGICAL TEST SCORES. CONCLUSIONS: THE ABSENCE OF ABETA DEPOSITION IN MANY PATIENTS WITH CHRONIC NEUROPSYCHOLOGICAL IMPAIRMENT AFTER TBI DOES NOT SUPPORT THE PREMISE THAT ABETA PATHOLOGY PROGRESSES OVER TIME IN THE TRAUMATIZED BRAIN. EARLY AND SEQUENTIAL (11)C-PIB PET EXAMINATION MAY CLARIFY THE TIME COURSE OF ABETA DEPOSITION IN THE TRAUMATIZED BRAIN AND THE RELATIONSHIP BETWEEN TRAUMATIC BRAIN INSULT AND SUBSEQUENT NEUROPSYCHOLOGICAL IMPAIRMENT. 2013 12 988 26 CHRONIC SLEEP DISTURBANCES ALTERS SLEEP STRUCTURE AND TAU PHOSPHORYLATION IN ABETAPP/PS1 AD MICE AND THEIR WILD-TYPE LITTERMATES. BACKGROUND: EMERGING EVIDENCE INDICATES THAT SLEEP DISORDERS ARE THE COMMON NON-COGNITIVE SYMPTOMS OF ALZHEIMER'S DISEASE (AD), AND THEY MAY CONTRIBUTE TO THE PATHOGENESIS OF THIS DISEASE. OBJECTIVE: IN THIS STUDY, WE AIM TO INVESTIGATE THE EFFECT OF CHRONIC SLEEP DEPRIVATION (CSD) ON AD-RELATED PATHOLOGIES WITH A FOCUS ON TAU PHOSPHORYLATION AND THE UNDERLYING DNA METHYLATION REGULATION. METHODS: ABETAPPSWE/PS1DELTAE9 AD MICE AND THEIR WILD-TYPE (WT) LITTERMATES WERE SUBJECTED TO A TWO-MONTH CSD FOLLOWED BY ELECTROENCEPHALOGRAPHY AND ELECTROMYOGRAPHY RECORDING. THE MICE WERE EXAMINED FOR LEARNING AND MEMORY EVALUATION, THEN PATHOLOGICAL, BIOCHEMICAL, AND EPIGENETIC ASSESSMENTS INCLUDING WESTERN BLOTTING, IMMUNOFLUORESCENCE, DOT BLOTTING, AND BISULFITE SEQUENCING. RESULTS: THE RESULTS SHOW THAT CSD CAUSED SLEEP DISTURBANCES SHOWN AS SLEEP PATTERN CHANGE, POOR SLEEP MAINTENANCE, AND INCREASED SLEEP FRAGMENTATION. CSD INCREASED TAU PHOSPHORYLATION AT DIFFERENT SITES AND INCREASED THE LEVEL OF TAU KINASES IN AD AND WT MICE. THE INCREASED EXPRESSION OF CYCLIN-DEPENDENT KINASE 5 (CDK5) MAY RESULT FROM DECREASED DNA METHYLATION OF CPG SITES IN THE PROMOTER REGION OF CDK5 GENE, WHICH MIGHT BE ASSOCIATED WITH THE DOWNREGULATION OF DNA METHYLTRANSFERASE 3A AND 3B. CONCLUSION: CSD ALTERED AD-RELATED TAU PHOSPHORYLATION THROUGH EPIGENETIC MODIFICATION OF TAU KINASE GENE. THE FINDINGS IN THIS STUDY MAY GIVE INSIGHTS INTO THE MECHANISMS UNDERLYING THE EFFECTS OF SLEEP DISTURBANCES ON AD PATHOLOGY AND PROVIDE NEW THERAPEUTIC TARGETS FOR THE TREATMENT OF THIS DISEASE. 2023 13 644 29 BIOPHARMACEUTICAL MONOTARGETING VERSUS 'UNIVERSAL TARGETING' OF LATE-ONSET ALZHEIMER'S DISEASE USING MIXTURES OF PLEIOTROPIC NATURAL COMPOUNDS. A FIVE-YEAR CLOSE READING OF THE SCIENTIFIC LITERATURE ON LATE-ONSET ALZHEIMER'S DISEASE (AD) HAS PROMPTED THE INVENTION OF A NOVEL THERAPEUTIC METHOD THAT BIOMECHANISTICALLY TARGETS THE TARGETABLE DISEASE-PROCESS TARGETS OF AD WITH ONE OR ANOTHER MIXTURE OF NON-TOXIC PLEIOTROPIC NATURAL COMPOUNDS. THE FEATURED MIXTURE HEREIN IS COMPRISED OF CURCUMIN, RESVERATROL, AND EGCG. THE MIXTURE'S TARGETS INCLUDE CENTRAL PATHOLOGICAL ELEMENTS OF AD (INCLUDING AMYLOID, TAU, SYNAPTIC DYSFUNCTION, OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, AND ABERRANT NEUROINFLAMMATION), MODIFIABLE RISK FACTORS, COMORBIDITIES, AND EPIGENETIC ELEMENTS. THE FEATURED MIXTURE AND OTHER SUCH MIXTURES ARE SUITABLE FOR LONG-TERM USE, AND MAY BE APPLIED TO ANY STAGE OF AD, INCLUDING PRIMARY AND SECONDARY PREVENTION. SUCH MIXTURES ALSO WOULD BE AMENABLE FOR USE AS PRE-TREATMENT, CO-TREATMENT, AND POST-TREATMENT APPLICATIONS WITH CERTAIN BIOPHARMACEUTICAL AGENTS. THE TARGETING FOCUS HERE IS THE MAJOR CREDIBLE HYPOTHESES OF AD. THE FOCUS OF FUTURE SUCH ARTICLES WILL INCLUDE OTHER AD-RELATED TARGETS, MODIFIABLE RISK FACTORS AND COMORBIDITIES, APOE4, EPIGENETIC FACTORS, BIOAVAILABILITY, DOSE RESPONSE, AND IMPLICATIONS FOR CLINICAL TESTING. THE "UNIVERSAL TARGETING" METHOD DESCRIBED HEREIN-THAT IS, "TARGETING THE TARGETABLE TARGETS" OF AD USING CERTAIN MIXTURES OF NATURAL COMPOUNDS-IS REPROGRAMMABLE AND THUS IS APPLICABLE TO OTHER CHRONIC NEUROLOGICAL CONDITIONS, INCLUDING PARKINSON'S DISEASE, VASCULAR DEMENTIA, ISCHEMIC-STROKE PREVENTION AND RECOVERY, AND SPORTS-RELATED HEAD INJURIES AND SEQUELAE LEADING TO CHRONIC TRAUMATIC ENCEPHALOPATHY. 2019 14 1600 27 DNA METHYLATION SIGNATURES OF ALZHEIMER'S DISEASE NEUROPATHOLOGY IN THE CORTEX ARE PRIMARILY DRIVEN BY VARIATION IN NON-NEURONAL CELL-TYPES. ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISEASE CHARACTERIZED BY THE PROGRESSIVE ACCUMULATION OF AMYLOID-BETA AND NEUROFIBRILLARY TANGLES OF TAU IN THE NEOCORTEX. WE PROFILED DNA METHYLATION IN TWO REGIONS OF THE CORTEX FROM 631 DONORS, PERFORMING AN EPIGENOME-WIDE ASSOCIATION STUDY OF MULTIPLE MEASURES OF AD NEUROPATHOLOGY. WE META-ANALYZED OUR RESULTS WITH THOSE FROM PREVIOUS STUDIES OF DNA METHYLATION IN AD CORTEX (TOTAL N = 2013 DONORS), IDENTIFYING 334 CORTICAL DIFFERENTIALLY METHYLATED POSITIONS (DMPS) ASSOCIATED WITH AD PATHOLOGY INCLUDING METHYLOMIC VARIATION AT LOCI NOT PREVIOUSLY IMPLICATED IN DEMENTIA. WE SUBSEQUENTLY PROFILED DNA METHYLATION IN NEUN+ (NEURONAL-ENRICHED), SOX10+ (OLIGODENDROCYTE-ENRICHED) AND NEUN-/SOX10- (MICROGLIA- AND ASTROCYTE-ENRICHED) NUCLEI, FINDING THAT THE MAJORITY OF DMPS IDENTIFIED IN 'BULK' CORTEX TISSUE REFLECT DNA METHYLATION DIFFERENCES OCCURRING IN NON-NEURONAL CELLS. OUR STUDY HIGHLIGHTS THE POWER OF UTILIZING MULTIPLE MEASURES OF NEUROPATHOLOGY TO IDENTIFY EPIGENETIC SIGNATURES OF AD AND THE IMPORTANCE OF CHARACTERIZING DISEASE-ASSOCIATED VARIATION IN PURIFIED CELL-TYPES. 2022 15 2227 27 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 16 5837 31 STRESSED MITOCHONDRIA: A TARGET TO INTRUDE ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS THE INOPERABLE, INCAPACITATING, NEUROPSYCHIATRIC, AND DEGENERATIVE MANIFESTATION THAT DRASTICALLY AFFECTS HUMAN LIFE QUALITY. THE CURRENT MEDICATIONS TARGET EXTRA-NEURONAL SENILE PLAQUES, OXIDATIVE STRESS, NEUROINFLAMMATION, INTRANEURONAL NEUROFIBRILLARY TANGLES, CHOLINERGIC DEFICITS, AND EXCITOTOXICITY. AMONG NOVEL PATHWAYS AND TARGETS, BIOENERGETIC AND RESULTANT MITOCHONDRIAL DYSFUNCTION HAS BEEN RECOGNIZED AS ESSENTIAL FACTORS THAT DECIDE THE NEURONAL FATE AND CONSEQUENT NEURODEGENERATION IN AD. THE CRUCIAL ATTRIBUTES OF MITOCHONDRIA, INCLUDING BIOENERGESIS, SIGNALING, SENSING, INTEGRATING, AND TRANSMITTING BIOLOGICAL SIGNALS CONTRIBUTE TO OPTIMUM NETWORKING OF NEURONAL DYNAMICS AND MAKE THEM INDISPENSABLE FOR CELL SURVIVAL. IN AD, MITOCHONDRIAL DYSFUNCTION AND MITOPHAGY ARE A PRELIMINARY AND CRITICAL EVENT THAT AGGRAVATES THE PATHOLOGICAL CASCADE. STRESS IS KNOWN TO PROMOTE AND EXAGGERATE THE NEUROPATHOLOGICAL ALTERATION DURING NEURODEGENERATION AND METABOLIC IMPAIRMENTS, ESPECIALLY IN THE CORTICO-LIMBIC SYSTEM, BESIDES ADVERSELY AFFECTING THE NORMAL PHYSIOLOGY AND MITOCHONDRIAL DYNAMICS. STRESS INVOLVES THE ALLOCATION OF ENERGY RESOURCES FOR NEURONAL SURVIVAL. CHRONIC AND AGGRAVATED STRESS RESPONSE LEADS TO EXCESSIVE RELEASE OF GLUCOCORTICOIDS BY ACTIVATION OF THE HYPOTHALAMIC-PITUITARYADRENAL (HPA) AXIS. BY ACTING THROUGH THEIR RECEPTORS, GLUCOCORTICOIDS INFLUENCE ADVERSE MITOCHONDRIAL CHANGES AND ALTER MTDNA TRANSCRIPTION, MTRNA EXPRESSION, HIPPOCAMPAL MITOCHONDRIAL NETWORK, AND ULTIMATELY MITOCHONDRIAL PHYSIOLOGY. CHRONIC STRESS ALSO AFFECTS MITOCHONDRIAL DYNAMICS BY CHANGING METABOLIC AND NEURO-ENDOCRINAL SIGNALLING, AGGRAVATING OXIDATIVE STRESS, PROVOKING INFLAMMATORY MEDIATORS, ALTERING TROPIC FACTORS, INFLUENCING GENE EXPRESSION, AND MODIFYING EPIGENETIC PATHWAYS. THUS, EXPLORING CHRONIC STRESS-INDUCED GLUCOCORTICOID DYSREGULATION AND RESULTANT BIO-BEHAVIORAL AND PSYCHOSOMATIC MITOCHONDRIAL ALTERATIONS MAY BE A FEASIBLE NARRATIVE TO INVESTIGATE AND UNRAVEL THE MYSTERIOUS PATHOBIOLOGY OF AD. 2021 17 4348 41 MIR-146A DYSREGULATES ENERGY METABOLISM DURING NEUROINFLAMMATION. ALZHEIMER'S DISEASE (AD) AND OTHER NEURODEGENERATIVE DISEASES ARE CHARACTERIZED BY CHRONIC NEUROINFLAMMATION AND A REDUCTION IN BRAIN ENERGY METABOLISM. AN IMPORTANT ROLE HAS EMERGED FOR SMALL, NON-CODING RNA MOLECULES KNOWN AS MICRORNAS (MIRNAS) IN THE PATHOPHYSIOLOGY OF MANY NEURODEGENERATIVE DISORDERS. AS EPIGENETIC REGULATORS, MIRNAS POSSESS THE CAPACITY TO REGULATE AND FINE TUNE PROTEIN PRODUCTION BY INHIBITING TRANSLATION. SEVERAL MIRNAS, WHICH INCLUDE MIR-146A, ARE ELEVATED IN THE BRAIN, CSF, AND PLASMA OF AD PATIENTS. MIR-146A PARTICIPATES IN PATHWAYS THAT REGULATE IMMUNE ACTIVATION AND HAS SEVERAL MRNA TARGETS WHICH ENCODE FOR PROTEINS INVOLVED IN CELLULAR ENERGY METABOLISM. AN ADDITIONAL ROLE FOR EXTRACELLULAR VESICLES (EVS) HAS ALSO EMERGED IN THE PROGRESSION AD, AS EVS CAN TRANSFER FUNCTIONALLY ACTIVE PROTEINS AND RNAS FROM DISEASED TO HEALTHY CELLS. IN THE CURRENT STUDY, WE EXPOSED VARIOUS CELL TYPES PRESENT WITHIN THE CNS TO IMMUNOMODULATORY MOLECULES AND OBSERVED SIGNIFICANT UPREGULATION OF MIR-146A EXPRESSION, BOTH WITHIN CELLS AND WITHIN THEIR SECRETED EVS. FURTHER, WE ASSESSED THE EFFECTS OF MIR-146A OVEREXPRESSION ON BIOENERGETIC FUNCTION IN PRIMARY RAT GLIAL CELLS AND FOUND SIGNIFICANT REDUCTIONS IN OXIDATIVE PHOSPHORYLATION AND GLYCOLYSIS. LASTLY, WE CORRELATED MIR-146A EXPRESSION LEVELS WITHIN VARIOUS REGIONS OF THE AD BRAIN TO DISEASE STAGING AND FOUND SIGNIFICANT, POSITIVE CORRELATIONS. THESE NOVEL RESULTS DEMONSTRATE THAT THE MODULATION OF MIR-146A IN RESPONSE TO NEUROINFLAMMATORY STIMULI MAY MEDIATE THE LOSS OF MITOCHONDRIAL INTEGRITY AND FUNCTION IN CELLS, THEREBY CONTRIBUTING TO THE PROGRESSION OF BETA-AMYLOID AND TAU PATHOLOGY IN THE AD BRAIN. MULTIPLE INFLAMMATORY STIMULI CAN UPREGULATE MIRNA-146A EXPRESSION WITHIN NEURONS, MIXED GLIAL CELLS, AND BRAIN ENDOTHELIAL CELLS, WHICH IS EITHER RETAINED WITHIN THESE CELLS OR RELEASED FROM THEM AS EXTRACELLULAR VESICLE CARGO. THE UPREGULATION OF MIR-146A DISRUPTS CELLULAR BIOENERGETICS IN MIXED GLIAL CELLS. THIS MECHANISM MAY PLAY A CRITICAL ROLE IN THE NEUROINFLAMMATORY RESPONSE OBSERVED DURING ALZHEIMER'S DISEASE. 2022 18 6058 38 THE DEFICIENCY OF N6-METHYLADENOSINE DEMETHYLASE ALKBH5 ENHANCES THE NEURODEGENERATIVE DAMAGE INDUCED BY COBALT. COBALT EXPOSURE, EVEN AT LOW CONCENTRATIONS, INDUCES NEURODEGENERATIVE DAMAGE, SUCH AS ALZHEIMER'S DISEASE (AD). THE SPECIFIC UNDERLYING MECHANISMS REMAIN UNCLEAR. OUR PREVIOUS STUDY DEMONSTRATED THAT M(6)A METHYLATION ALTERATION IS INVOLVED IN COBALT-INDUCED NEURODEGENERATIVE DAMAGE, SUCH AS IN AD. HOWEVER, THE ROLE OF M(6)A RNA METHYLATION AND ITS UNDERLYING MECHANISMS ARE POORLY UNDERSTOOD. IN THIS STUDY, BOTH EPIDEMIOLOGICAL AND LABORATORY STUDIES SHOWED THAT COBALT EXPOSURE COULD DOWNREGULATE THE EXPRESSION OF THE M(6)A DEMETHYLASE ALKBH5, SUGGESTING A KEY ROLE FOR ALKBH5. MOREOVER, METHYLATED RNA IMMUNOPRECIPITATION AND SEQUENCING (MERIP-SEQ) ANALYSIS REVEALED THAT ALKBH5 DEFICIENCY IS ASSOCIATED WITH NEURODEGENERATIVE DISEASES. KEGG PATHWAY AND GENE ONTOLOGY ANALYSES FURTHER REVEALED THAT THE DIFFERENTIALLY M(6)A-MODIFIED GENES RESULTING FROM ALKBH5 DOWNREGULATION AND COBALT EXPOSURE WERE AGGREGATED IN THE PATHWAYS OF PROLIFERATION, APOPTOSIS, AND AUTOPHAGY. SUBSEQUENTLY, ALKBH5 DEFICIENCY WAS SHOWN TO EXACERBATE CELL VIABILITY DECLINE, MOTIVATE CELL APOPTOSIS AND ATTENUATE CELL AUTOPHAGY INDUCED BY COBALT WITH EXPERIMENTAL TECHNIQUES OF GENE OVEREXPRESSION/INHIBITION. IN ADDITION, MORPHOLOGICAL CHANGES IN NEURONS AND THE EXPRESSION OF AD-RELATED PROTEINS, SUCH AS APP, P-TAU, AND TAU, IN THE CEREBRAL HIPPOCAMPUS OF WILD-TYPE AND ALKBH5 KNOCKOUT MICE AFTER CHRONIC COBALT EXPOSURE WERE ALSO INVESTIGATED. BOTH IN VITRO AND IN VIVO RESULTS SHOWED THAT LOWER EXPRESSION OF ALKBH5 AGGRAVATED COBALT-INDUCED NEURODEGENERATIVE DAMAGE. THESE RESULTS SUGGEST THAT ALKBH5, AS AN EPIGENETIC REGULATOR, COULD BE A POTENTIAL TARGET FOR ALLEVIATING COBALT-INDUCED NEURODEGENERATIVE DAMAGE. IN ADDITION, WE PROPOSE A NOVEL STRATEGY FOR THE PREVENTION AND TREATMENT OF ENVIRONMENTAL TOXICANT-RELATED NEURODEGENERATION FROM AN EPIGENETIC PERSPECTIVE. 2023 19 1560 29 DNA METHYLATION OF ALZHEIMER DISEASE AND TAUOPATHY-RELATED GENES IN POSTMORTEM BRAIN. DNA METHYLATION OCCURS PREDOMINANTLY AT CYTOSINES THAT PRECEDE GUANINES IN DINUCLEOTIDE CPG SITES; IT IS ONE OF THE MOST IMPORTANT MECHANISMS FOR EPIGENETIC DNA REGULATION DURING NORMAL DEVELOPMENT AND FOR ABERRANT DNA IN CANCER. TO DETERMINE THE FEASIBILITY OF DNA METHYLATION STUDIES IN THE POSTMORTEM HUMAN BRAIN, WE EVALUATED BRAIN SAMPLES WITH VARIABLE POSTMORTEM ARTIFICIALLY INCREASED DELAYS UP TO 48 HOURS. DNA METHYLATION WAS ANALYZED IN SELECTED REGIONS OF MAPT, APP, AND PSEN1 IN THE FRONTAL CORTEX AND HIPPOCAMPUS OF CONTROLS (N=26) AND THOSE WITH ALZHEIMER DISEASE AT STAGES I TO II (N=17); ALZHEIMER DISEASE AT STAGES III TO IV (N=15); ALZHEIMER DISEASE AT STAGES V TO VI (N=12); ARGYROPHILIC GRAIN DISEASE (N=10); FRONTOTEMPORAL LOBAR DEGENERATION LINKED TO TAU MUTATIONS (N=6); FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-IMMUNOREACTIVE INCLUSIONS (N=4); FRONTOTEMPORAL LOBAR DEGENERATION WITH MOTOR NEURON DISEASE (N=3); PICK DISEASE (N=3); PARKINSON DISEASE (N=8); DEMENTIA WITH LEWY BODIES, PURE FORM (N=5); AND DEMENTIA WITH LEWY BODIES, COMMON FORM (N=15). UCHL1 (UBIQUITIN CARBOXYL-TERMINAL HYDROLASE 1 GENE) WAS ANALYZED IN THE FRONTAL CORTEX OF CONTROLS AND THOSE WITH PARKINSON DISEASE AND RELATED SYNUCLEINOPATHIES. DNA METHYLATION SITES WERE VERY REPRODUCIBLE IN EVERY CASE. NO DIFFERENCES IN THE PERCENTAGE OF CPG METHYLATION WERE FOUND BETWEEN CONTROL AND DISEASE SAMPLES OR AMONG THE DIFFERENT PATHOLOGICAL ENTITIES IN ANY REGION ANALYZED. BECAUSE SMALL CHANGES IN METHYLATION OF DNA PROMOTERS IN VULNERABLE CELLS MIGHT HAVE NOT BEEN DETECTED IN TOTAL HOMOGENATES, HOWEVER, THESE RESULTS SHOULD BE INTERPRETED WITH CAUTION, PARTICULARLY AS THEY RELATE TO CHRONIC DEGENERATIVE DISEASES IN WHICH SMALL MODIFICATIONS MAY BE SUFFICIENT TO MODULATE DISEASE PROGRESSION. 2009 20 165 24 ABNORMAL HOMOCYSTEINE METABOLISM: AN INSIGHT OF ALZHEIMER'S DISEASE FROM DNA METHYLATION. ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISEASE IN THE CENTRAL NERVOUS SYSTEM THAT HAS COMPLEX PATHOGENESIS IN THE ELDERLY. THE CURRENT REVIEW FOCUSES ON THE EPIGENETIC MECHANISMS OF AD, ACCORDING TO THE LATEST FINDINGS. ONE OF THE BEST-CHARACTERIZED CHROMATIN MODIFICATIONS IN EPIGENETIC MECHANISMS IS DNA METHYLATION. HIGHLY REPLICABLE DATA SHOWS THAT AD OCCURRENCE IS OFTEN ACCOMPANIED BY METHYLATION LEVEL CHANGES OF THE AD-RELATED GENE. HOMOCYSTEINE (HCY) IS NOT ONLY AN INTERMEDIATE PRODUCT OF ONE-CARBON METABOLISM BUT ALSO AN IMPORTANT INDEPENDENT RISK FACTOR OF AD; IT CAN AFFECT THE COGNITIVE FUNCTION OF THE BRAIN BY CHANGING THE ONE-CARBON METABOLISM AND INTERFERING WITH THE DNA METHYLATION PROCESS, RESULTING IN CEREBROVASCULAR DISEASE. IN GENERAL, HCY MAY BE AN ENVIRONMENTAL FACTOR THAT AFFECTS AD VIA THE DNA METHYLATION PATHWAY WITH A SERIES OF CHANGES IN AD-RELATED SUBSTANCE. THIS REVIEW WILL CONCENTRATE ON THE RELATION BETWEEN DNA METHYLATION AND HCY AND TRY TO FIGURE OUT THEIR RULE IN THE PATHOPHYSIOLOGY OF AD. 2020