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MECHANISMS OF AGE-RELATED COGNITIVE CHANGE AND TARGETS FOR INTERVENTION: EPIGENETICS MADIHAH MOHAMAD, EIZZATI ARIPIN, SITI ZULAIHA ABU BAKAR

MECHANISMS OF AGE-RELATED COGNITIVE CHANGE AND TARGETS FOR INTERVENTION: EPIGENETICS MADIHAH MOHAMAD, EIZZATI ARIPIN, SITI ZULAIHA ABU BAKAR

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MECHANISMS OF AGE-RELATED COGNITIVE CHANGE AND TARGETS FOR INTERVENTION: EPIGENETICSMADIHAH MOHAMAD, EIZZATI ARIPIN, SITI ZULAIHA ABU BAKARAGING AND EPIGENETICChanges- cognitive fx, brain anatomy, physiology and neurochemistry

Rate + magnitude of changes varies across individuals, brain regions and functional domains

Epigenetic mech.- potent regulators of gene expression, unrelated to changes in DNA sequence.

Cognitive Neuroepigenetics- research on psychiatric illness, addiction, neurodegenerative diseases.

Research on potential epigenetic contributions to age-related cognitive change has only recently emerged

Cognitive Aging Summit IIU. of Alabama, Birmingham: survey on DNA mathylation and other epigenetic mech in learning and memory, cog epigenetic of aging

U of California, Santa Barbara: role of miRNAs affecting large scale protein networks in aging process

Broad Ins. And Massachusetts Ins. of Tech.: dev of preclinical strategies in mouse models targeting reg of histone acethylation to repress transc + translation to reduce synaptic plasticity in aged brain.

Columbia U: human cognitive aging, signif. of regional vulnerability in hippocampusin relation of age mediated effects on mediators of histone acethylation.

Concluding comments: major themes, future directions and challenges to progress.EPIGENETIC MECHANISMS IN MEMORY FORMATION

Age-related memory decline = prominently in declarative/episodic and working memory,memory modalities = based largely in the hippocampus and prefrontal cortexMemory and synaptic plasticity associated with transcription of immediate-early genes (IEGs) including :Arc (activity-regulated cytoskeletal gene)Zi1268 (also known as nerve growth factor inducible-A, and early growth response gene)BDNF (brain-derived neurotrophic factorConsolidation of memory = prevented by blocking the expression oh these genesNormal aging = results from decreased immediate-early gene expression (as seen in some models of memory disorders)The relevant epigenetic mechanisms include histone posttranslational modifications and DNA methylation (recently discovered) = to control hippocampal synaptic plasticity and long-term memory formationInvolving :the covalent chemical modification of histones by histone acetyltransferases and histone deacetylases (HDACs)covalent modification of DNA by DNA methyltransferasesEpigenetic mechanisms = powerful controllers of memory-associated gene transcription (typically result : transcriptional silencing + loss of gene function)aging-related cognitive dysfunction = caused by dysregulation of epigenetic control mechanisms and accumulation of aberrant epigenetic markstranscription of key memory-promoting genes = decline during agingAn assessment of memory formation-associated DNA methylation in the aged rat hippocampus (Carol Barnes research group ) = to determine if aging is associated with a disruption of epigenomic signallingProcess : 1st group of animals screened using spatial version of the Morris swim task = to confirm that the aged animals exhibited impaired memoryAnimals explored (training) a novel environment for 5 mins (a week later) = treatment that results in both new memory formationAnimals rested in cage for 25 minsDecapitation under deep isoflurane anesthesiaExtraction and dissection of hippocampus into CA1 and dentate gyrus samples = to get DNA and processed for bisulfite modification, methylation state was determined for the Arc gene via sequencing of control and bisulfite-treated DNA2nd group (directly from cage) = to determine resting levels of DNA methylation of the Arc gene in hippocampus

Results :Revealed a distinct pattern of methylation of the Arc gene within the aged hippocampusIn CA1 = young adult and aged rat showed significant and comparable demethlation of Arc DNA (in response to spatial exploration)In dentate gyrus = aged rats showed less DNA methylation + significantly increased methylation of Arc gene following spatial learningAging = accompanied by significant alterations in epigenomic signaling + changes specifically targeting the memory-promoting gene Arc

MIRNAs Hold The Potential To Reveal A Genetic Architecture Of AgingBiological aging: Internal biological clockAccumulation of insults to the organismLifespan of a species:Biological agingLife span of an individual:Specific environmental circumstances (accumulated insults)Individual differences of biological clockThese 2 facets operate at every level of biological hierarchy (genes, proteins, cells, organs, systems, organisms).

The 1st of relevant genetic pathways:Discovered in 1993Cynthia Kenyon found that a single gene mutation in daf-2 could double the lifespan of Caenorhabditis elegansCould be reversed by a second mutation of daf-16m.The following relevant genetic pathway:Using the previous systemDiscovered by Victor AmbroseA novel class of posttranscriptional gene regulators called miRNAs.Victor Ambroses discovery:miRNAs form RNA-RNA duplex housed in RNA-induced silencing complex partially silencing the translation of target mRNAsA single miRNA targets multiple mRNAsRecent findings suggest that their exquisite tissue specificity may open a door to the congnitive aging problemAlthough several studies indicate that miRNA profiles change with age, the precise association of specific aging models is unclearA coherent set of pathways related to aging will emergemiRNA levels can be exogenously manipulated;Upregulated delivery of precursor miRNAsDownregulated delivery of locked nucleic acid antisense sequencesSets of miRNA targets are often functionally relatedDemonstrated property in cancer:Sets of mRNA targets that are all related to p53 pathway in onco-miR, miR-21 (16)miR-128 = tumor suppressor miRNA that targets the functionally related genes within tyrosine kinase receptor pathwaysShows the role of miRNAs in modulating entire networks in a distributed and robust manner by main small changes in protein levels among many components of network

miRNA approach to modulating function differs radically from a classic pharmacological approachThe flaws in pharmaceutical approach:Pathways are highly redundantInhibiting any single component compensatory responseIdentify & manipulate miRNAs that target multiple mRNAs (related to aging) modulate some facets of aging

Genes related to aging at a cellular level are tumor suppressor genes:Frequent miRNA targetTheir depression reduced level of specific miRNAs accelerate an aging phenotypee.g. genes at the Ink4/Arf locus activated proliferation reduced anticancer mechanism may contribute to the attrition of stem cells with aging

miRNAs have important roles in stem cells as pluripotent cells pass through stages of increasingly restricted potential until they reach terminal differentiationBiological aging begins the moment cells exit pluripotencyPluripotency terminal differentiation can be tracked by a set of miRNA changesEach discrete stage in a cells lineage is marked by a defining miRNA profileUnraveling the complex target networks of miRNAs could offer important new insight into the aging process

Histone Acetylation and Histone Deacetylases in Mouse Models of NeurodegenrationAlzheimers disease (AD):Age related neurodegenrative disorder associated with severe memory impairmentProminent feature the progressive loss of forebrain neurons and deterioration of learning and memoryNo significantly effective treatment yetThe development of alternative therapeutic approaches is an absolute necessity

Epigenetic:Study of changes in gene expression that are mediated by mechanisms other than changes in DNA sequencee.g. chromatin remodeling patterns of gene expression are modulated via the alteration of chromatin structureIncreased histone acetylation more relaxed chromatin structure increased gene expressionHistone acetylation regulated by the opposing activities of 2 groups of enzymes (the histone acetyltransferase + HDACs)Class I HDACs (HDAC 1, 2, 3):Primarily found within nucleusRegulate histone acetylation + suppress gene expressionRecruited to the promoter regions of genes via transcriptional repressor and corepressor proteinsRecent studies histone acetylation learning and memoryIncreased histone acetylation after various learning paradigmsAfter HDACi treatment, facilitation of synaptic plasticity and memory formationThus, increased histone acetylation facilitates cognitive functionCK-p25 mouse model experiment:Nonselective HDACi sodium butyrate improves cognitive performance (even after severe neurodegeneration)HDACis suberoylanilide hydroxamic acid + phenylbutyrate reinstate learning behaviour in AD mouseThey showed elevated H4 acetylation + increased production of proteins implicated in synaptic functionTreatment with HDACis has emerged as a promising new strategy for therapeutic intervention in neurodegeneration

Overexpression of HADC2 in mouse neurons striking impairment of memory formation + synaptic plasticity (not observed in overexpression of HDAC1) + reduced hippocampal H4K12 and H4K5 acetylation *other marks not affectedHDAC2 knockout mice (not HDAC1 knockout mice) increased H4K12 and H4K5 acetylation + enhanced learning, memory, synaptic plasticity + rare model of cognitive enhancementHDAC2:Learning and memorySynaptic plasticityRegulation of H4K12 (dysregulation is implicated in age-associated memory impairment)Enriched on the promoters of genes that are implicated in synaptic remodeling and plasticity or that are regulated by neuronal activity (based on immunoprecipitation)Administration of suberoylanilide hydroxamic acid fails to further increase synaptic plasticity in HDAC2 knockout mice HDAC2 appears to be the major target of HDACi in eliciting memory enhancementConclusion from the observations:Dysregulation of chromatin remodeling cognitive impairmentChronic abnormalities in histone acetylation (dysfunction of HDAC or histone acetyltransferase enzymes) aberrant expression of genes for learning and memory + synaptic plasticity + synaptogenesis brain in a locked state (i.e. probability of the activity-dependent expression of plasticity is reduced)

The Dentate Gyrus in Cognitive Aging: Is Histone Acetylation The Molecular Link??The Dentate Gyrus and Cognitive AgingFrontal cortex and the hippocampal formation: strongly implicated in age-related memory declineHippocampal formation made up of:Entorhinal cortexDentate gyrusCA1 and CA3 pyramidal cell fieldssubiculumThe Dentate Gyrus and Cognitive Aging

The Dentate Gyrus and Cognitive Aging

The Dentate Gyrus and Cognitive AgingEach hippocampal subregion expresses a unique malecular profile this is why individual subregions are differentially vulnerable to diseaseAge-related hippocampal dysf(x) due to:Absence of neuron lossPathognomonic histological featuresThe Aging Dentate Gyrus and Histone AcetylationHistone acetylation epigenetically regulates transcriptionDentate gyrus differentially engages this pathwayUnique feature of dentate gyrus is, it supports neurogenesis late into development, even into postnatal periodHistone acetylation is a critical pathway for neuronal differentioationAge- related defects in histone acetylation play an important role in age-related dentate gyrus dysf(x)The Aging Dentate Gyrus and Histone AcetylationAging dentate gyrus age-related changes in molecules that regulate histone acetylationTherapeutic intervention:Any interventions that ameliorate age-related hippocampal dysf(x), will improve the f(x) of dentate gyrus (via histone acetylation pathway)Physical excersiceImproving glucose control in DMConcluding CommentsCognitive aging is multifarious phenomenonKey challenges:To identify the precise epigenetic changesTo determine the time scale of their influenceTo define how epigenetic mechanisms achieve specificity in the coordination of experience-dependent gene expression profile