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 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 3 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 4 1829 36 EFFECTS OF INHIBITING ASTROCYTES AND BET/BRD4 CHROMATIN READER ON SPATIAL MEMORY AND SYNAPTIC PROTEINS IN RATS WITH ALZHEIMER'S DISEASE. COMMUNICATION BETWEEN ASTROCYTES AND NEURONS HAS A PROFOUND EFFECT ON THE PATHOPHYSIOLOGY OF ALZHEIMER'S DISEASE (AD). ASTROCYTES REGULATE HOMEOSTASIS AND INCREASE SYNAPTIC PLASTICITY IN PHYSIOLOGICAL SITUATIONS, HOWEVER, THEY BECOME ACTIVATED DURING THE PROGRESSION OF AD. WHETHER OR NOT THESE REACTIONS ARE SUPPORTIVE OR DETRIMENTAL FOR THE CENTRAL NERVOUS SYSTEM HAVE NOT BEEN UNDERSTOOD YET. CONSIDERING EPIGENETIC REGULATION OF NEUROINFLAMMATORY GENES BY CHROMATIN READERS, PARTICULARLY BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) FAMILY, HERE WE EXAMINED THE EFFECT OF CHRONIC CO-INHIBITION OF ASTROCYTES METABOLISM (WITH FLUOROCITRATE) AND ALSO BRD4 (WITH JQ1) ON COGNITION DEFICIT AT EARLY STAGES OF AD. FORTY ADULT MALE WISTAR RATS UNDERWENT STEREOTAXIC CANNULATION FOR INDUCING AD BY INTRAHIPPOCAMPAL INJECTION OF ABETA(1-42) (4 MUG/8 MUL/RAT). THEN ANIMALS WERE DIVIDED INTO FIVE GROUPS OF SALINE+DMSO, ABETA + SALINE+DMSO, ABETA + JQ1, ABETA + FC (FLUOROCITRATE), AND ABETA + JQ1 + FC AND RECEIVED THE RELATED TREATMENTS. TWO WEEKS LATER, SPATIAL MEMORY WAS RECORDED BY MORRIS WATER MAZE (MWM), AND THE LEVELS OF PHOSPHORYLATED CYCLIC-AMP RESPONSE ELEMENT BINDING PROTEIN (CREB), POSTSYNAPTIC DENSITY 95 (PSD95), SYNAPTOPHYSIN (SYP), AND TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) WERE MEASURED IN THE HIPPOCAMPUS BY WESTERN BLOTTING AND RT-QPCR. ADMINISTRATION OF JQ1 SIGNIFICANTLY IMPROVED BOTH ACQUISITION AND RETRIEVAL OF SPATIAL MEMORY, WHICH WERE EVIDENT BY DECREASED ESCAPE LATENCY AND INCREASED TOTAL TIME SPENT (TTS) IN TARGET QUADRANT, AND SIGNIFICANT RISE IN P-CREB, PSD95, AND SYNAPTOPHYSIN COMPARED WITH ABETA + SALINE+DMSO GROUP. IN CONTRAST, BOTH GROUPS RECEIVING FC DEMONSTRATED MEMORY DECLINE, AND REDUCTION IN P-CREB, PSD95 AND SYNAPTOPHYSIN IN PARALLEL WITH INCREASE IN TNF-ALPHA. OUR DATA INDICATE THAT CHRONIC INHIBITION OF BRD4 SIGNIFICANTLY RESTORES MEMORY IMPAIRED BY AMYLOID BETA PARTLY VIA CREB SIGNALING AND UPREGULATING SYNAPTIC PROTEINS OF PSD95 AND SYNAPTOPHYSIN. HOWEVER, INHIBITION OF ASTROCYTES NULLIFIES THE MEMORY-BOOSTING EFFECTS OF JQ1 AND REDUCES CREB/PSD95/SYNAPTOPHYSIN LEVELS IN HIPPOCAMPUS. 2022 5 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 6 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 7 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 8 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 9 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 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 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 12 1201 33 CORTICOTROPIN-RELEASING FACTOR RECEPTOR-1 MODULATES BIOMARKERS OF DNA OXIDATION IN ALZHEIMER'S DISEASE MICE. INCREASED PRODUCTION OF HYDROXYL RADICAL IS THE MAIN SOURCE OF OXIDATIVE DAMAGE IN MAMMALIAN DNA THAT ACCUMULATES IN ALZHEIMER'S DISEASE (AD). REACTIVE OXYGEN SPECIES (ROS) REACT WITH BOTH NUCLEAR DNA (NDNA) AND MITOCHONDRIAL DNA (MTDNA) TO GENERATE 8-HYDROXY-2'-DEOXYGUANOSINE (8-OHDG), BOTH OF WHICH CAN BE MEASURED IN THE URINE. KNOWLEDGE OF THIS PATHWAY HAS POSITIONED MEASUREMENT OF URINE 8-OHDG AS A RELIABLE INDEX OF DNA OXIDATION AND A POTENTIAL BIOMARKER TARGET FOR TRACKING EARLY CELLULAR DYSFUNCTION IN AD. FURTHERMORE, EPIGENETIC STUDIES DEMONSTRATE DECREASED GLOBAL DNA METHYLATION LEVELS (E.G. 5-METHYL-2'-DEOXYCYTIDINE, 5-MDC) IN AD TISSUES. MOREOVER, STRESS HORMONES CAN ACTIVATE NEURONAL OXIDATIVE STRESS WHICH WILL STIMULATE THE RELEASE OF ADDITIONAL STRESS HORMONES AND RESULT IN DAMAGES TO HIPPOCAMPAL NEURONS IN THE AD BRAIN. OUR PREVIOUS WORK SUGGESTS THAT TREATING AD TRANSGENIC MICE THE TYPE-1 CORTICOTROPIN-RELEASING FACTOR RECEPTOR (CRFR1) ANTAGONIST, R121919, TO REDUCE STRESS SIGNALING, PREVENTED ONSET OF COGNITIVE IMPAIRMENT, SYNAPTIC/DENDRITIC LOSS AND ABETA PLAQUE ACCUMULATION. THEREFORE, TO INVESTIGATE WHETHER LEVELS OF DNA OXIDATION CAN BE IMPACTED BY THE SAME THERAPEUTIC APPROACH, URINE LEVELS OF HYDROGEN PEROXIDE, 8-OHDG, 5-MDC AND TOTAL ANTIOXIDANT CAPACITY (TAC) WERE ANALYZED USING AN AD TG MOUSE MODEL. WE FOUND THAT TG ANIMALS HAD AN 80% INCREASE IN HYDROGEN PEROXIDE LEVELS COMPARED TO WILD TYPE (WT) COUNTERPARTS, AN EFFECT THAT COULD BE DRAMATICALLY REVERSED BY THE CHRONIC ADMINISTRATION WITH R121919. A SIGNIFICANT DECREASE OF 8-OHDG LEVELS WAS OBSERVED IN TG MICE TREATED WITH CRFR1 ANTAGONIST. COLLECTIVELY OUR DATA SUGGEST THAT THE BENEFICIAL EFFECTS OF CRFR1 ANTAGONISM SEEN IN TG MICE MAY BE MECHANISTICALLY LINKED TO THE MODULATION OF OXIDATIVE STRESS PATHWAYS. 2017 13 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 14 355 25 ALTERED MITOCHONDRIAL DNA METHYLATION AND MITOCHONDRIAL DNA COPY NUMBER IN AN APP/PS1 TRANSGENIC MOUSE MODEL OF ALZHEIMER DISEASE. ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISEASE AND MITOCHONDRIAL IMPAIRMENT IS A KEY FEATURE OF AD. THE MITOCHONDRIAL DNA (MTDNA) EPIGENETIC MECHANISM IS A RELATIVELY NEW FIELD COMPARED TO NUCLEAR DNA. THE RELATIONSHIP BETWEEN MTDNA EPIGENETIC MECHANISM AND AD HASN'T BEEN ESTABLISHED. SO WE ANALYZED THE MTDNA METHYLATION IN D-LOOP REGION AND 12 S RRNA GENE IN THE HIPPOCAMPI IN AMYLOID PRECURSOR PROTEIN/PRESENILIN 1 (APP/PS1) TRANSGENIC MICE BY BISULFITE PYROSEQUENCING. MITOCHONDRIAL DNA COPY NUMBER AND GENE EXPRESSION WERE STUDIED BY QUANTITATIVE REAL-TIME PCR (QRT-PCR). WE OBSERVED A DECREASE IN THE DISPLACEMENT LOOP (D-LOOP) METHYLATION AND AN INCREASE IN 12 S RRNA GENE METHYLATION, WHILE BOTH THE MTDNA COPY NUMBER AND THE MITOCHONDRIAL GENE EXPRESSION WERE REDUCED IN APP/PS1 TRANSGENIC MICE. IN SUMMARY, THE PRESENT FINDING SUGGEST THAT MTDNA METHYLATION MAY PLAY A ROLE IN AD PATHOLOGY, WHICH WARRANTS LARGER FUTURE INVESTIGATIONS. 2019 15 988 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 16 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 17 280 34 AGE-RELATED MIRNAS DYSREGULATION AND ABNORMAL BACE1 EXPRESSION FOLLOWING PB EXPOSURE IN ADOLESCENT MICE. NUMBERS OF EMERGING EVIDENCE SUGGEST THAT LEAD (PB) EXPOSURE CONTRIBUTES TO COGNITIVE DECLINE AND MIGHT ALSO INCREASE THE RISK OF ALZHEIMER'S DISEASE (AD) DEMENTIA IN THE ELDERLY BY INCREASING THE BETA-AMYLOID BURDEN. HERE, WE AIMED TO CHARACTERIZE THE EFFECTS OF PB ON THE POST-TRANSCRIPTIONAL REGULATORS, MICRORNAS (MIRNAS), WHICH MAY PARTICIPATE IN AD PATHOGENESIS. AT FIRST, EARLY CHRONIC PB EXPOSURE ON NEURONAL MIRNAS EXPRESSION WITH INCREASING AGING WAS PROFILED TO ELUCIDATE THE ASSOCIATION OF THREE SELECTED MIRNAS WITH BETA-SITE APP-CLEAVING ENZYME 1(BACE1), A RATE-LIMITING ENZYME FOR BETA-AMYLOID (ABETA) PRODUCTION. NEXT, WE VERIFIED CHANGES IN BACE1 WERE OBSERVED BY REGULATING MIRNAS EXPRESSION IN VITRO. WHILE PB PROMOTED BACE1 LEVELS, BACE1 LEVELS WERE REDUCED IN SH-SY5Y CELLS WITH MIR-124-3P MIMIC, SUGGESTING FOR THE FIRST TIME THAT MIR-124-3P/BACE1 PATHWAY MODULATION IS CRITICALLY INVOLVED IN PB-INDUCED AD-LIKE AMYLOIDOGENIC PROCESSING. FINDINGS FROM THIS STUDY COULD PROVIDE NEW INSIGHT INTO THE MOLECULAR MECHANISMS OF PB-ASSOCIATED NEURODEGENERATIVE PATHOGENESIS FROM AN EPIGENETIC PERSPECTIVE. 2022 18 165 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 19 1427 26 DIFFERENTIAL EFFECTS OF CHRONIC IMMUNOSUPPRESSION ON BEHAVIORAL, EPIGENETIC, AND ALZHEIMER'S DISEASE-ASSOCIATED MARKERS IN 3XTG-AD MICE. BACKGROUND: CIRCULATING AUTOANTIBODIES AND SEX-DEPENDENT DISCREPANCY IN PREVALENCE ARE UNEXPLAINED PHENOMENA OF ALZHEIMER'S DISEASE (AD). USING THE 3XTG-AD MOUSE MODEL, WE REPORTED THAT ADULT MALES SHOW EARLY MANIFESTATIONS OF SYSTEMIC AUTOIMMUNITY, INCREASED EMOTIONAL REACTIVITY, ENHANCED EXPRESSION OF THE HISTONE VARIANT MACROH2A1 IN THE CEREBRAL CORTEX, AND LOSS OF PLAQUE/TANGLE PATHOLOGY. CONVERSELY, ADULT FEMALES DISPLAY LESS SEVERE AUTOIMMUNITY AND RETAIN THEIR AD-LIKE PHENOTYPE. THIS STUDY EXAMINES THE LINK BETWEEN IMMUNITY AND OTHER TRAITS OF THE CURRENT 3XTG-AD MODEL. METHODS: YOUNG 3XTG-AD AND WILD-TYPE MICE DRANK A SUCROSE-LACED 0.4 MG/ML SOLUTION OF THE IMMUNOSUPPRESSANT CYCLOPHOSPHAMIDE ON WEEKENDS FOR 5 MONTHS. AFTER BEHAVIORAL PHENOTYPING AT 2 AND 6 MONTHS OF AGE, WE ASSESSED ORGAN MASS, SEROLOGIC MARKERS OF AUTOIMMUNITY, MOLECULAR MARKERS OF EARLY AD PATHOLOGY, AND EXPRESSION OF GENES ASSOCIATED WITH NEURODEGENERATION. RESULTS: CHRONIC IMMUNOSUPPRESSION PREVENTED HEMATOCRIT DROP AND REDUCED SOLUBLE ABETA IN 3XTG-AD MALES WHILE NORMALIZING THE EXPRESSION OF HISTONE VARIANT MACROH2A1 IN 3XTG-AD FEMALES. THIS TREATMENT ALSO REDUCED HEPATOSPLENOMEGALY, LOWERED AUTOANTIBODY LEVELS, AND INCREASED THE EFFECTOR T CELL POPULATION WHILE DECREASING THE PROPORTION OF REGULATORY T CELLS IN BOTH SEXES. EXPOSURE TO CYCLOPHOSPHAMIDE, HOWEVER, NEITHER PREVENTED REDUCED BRAIN MASS AND BDNF EXPRESSION NOR NORMALIZED INCREASED TAU AND ANXIETY-RELATED BEHAVIORS. CONCLUSION: THE RESULTS SUGGEST THAT SYSTEMIC AUTOIMMUNITY INCREASES SOLUBLE ABETA PRODUCTION AND AFFECTS TRANSCRIPTIONAL REGULATION OF MACROH2A1 IN A SEX-RELATED MANNER. DESPITE THE COMPLEXITY OF MULTISYSTEM INTERACTIONS, 3XTG-AD MICE CAN BE A USEFUL IN VIVO MODEL FOR EXPLORING THE REGULATORY ROLE OF AUTOIMMUNITY IN THE ETIOLOGY OF AD-LIKE NEURODEGENERATIVE DISORDERS. 2021 20 1317 23 DELTAFOSB REGULATES GENE EXPRESSION AND COGNITIVE DYSFUNCTION IN A MOUSE MODEL OF ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS CHARACTERIZED BY COGNITIVE DECLINE AND 5- TO 10-FOLD INCREASED SEIZURE INCIDENCE. HOW SEIZURES CONTRIBUTE TO COGNITIVE DECLINE IN AD OR OTHER DISORDERS IS UNCLEAR. WE SHOW THAT SPONTANEOUS SEIZURES INCREASE EXPRESSION OF DELTAFOSB, A HIGHLY STABLE FOS-FAMILY TRANSCRIPTION FACTOR, IN THE HIPPOCAMPUS OF AN AD MOUSE MODEL. DELTAFOSB SUPPRESSED EXPRESSION OF THE IMMEDIATE EARLY GENE C-FOS, WHICH IS CRITICAL FOR PLASTICITY AND COGNITION, BY BINDING ITS PROMOTER AND TRIGGERING HISTONE DEACETYLATION. ACUTE HISTONE DEACETYLASE (HDAC) INHIBITION OR INHIBITION OF DELTAFOSB ACTIVITY RESTORED C-FOS INDUCTION AND IMPROVED COGNITION IN AD MICE. ADMINISTRATION OF SEIZURE-INDUCING AGENTS TO NONTRANSGENIC MICE ALSO RESULTED IN DELTAFOSB-MEDIATED SUPPRESSION OF C-FOS, SUGGESTING THAT THIS MECHANISM IS NOT CONFINED TO AD MICE. THESE RESULTS EXPLAIN OBSERVATIONS THAT C-FOS EXPRESSION INCREASES AFTER ACUTE NEURONAL ACTIVITY BUT DECREASES WITH CHRONIC ACTIVITY. MOREOVER, THESE RESULTS INDICATE A GENERAL MECHANISM BY WHICH SEIZURES CONTRIBUTE TO PERSISTENT COGNITIVE DEFICITS, EVEN DURING SEIZURE-FREE PERIODS. 2017