MECHANISMS OF AGE-RELATED COGNITIVE CHANGE AND TARGETS FOR INTERVENTION: EPIGENETICS
Sponsored Links
This presentation is the property of its rightful owner.
1 / 31

MECHANISMS OF AGE-RELATED COGNITIVE CHANGE AND TARGETS FOR INTERVENTION: EPIGENETICS PowerPoint PPT Presentation


  • 99 Views
  • Uploaded on
  • Presentation posted in: General

MECHANISMS OF AGE-RELATED COGNITIVE CHANGE AND TARGETS FOR INTERVENTION: EPIGENETICS. MADIHAH MOHAMAD, EIZZATI ARIPIN, SITI ZULAIHA ABU BAKAR. AGING AND EPIGENETIC. Changes- cognitive fx , brain anatomy, physiology and neurochemistry

Download Presentation

MECHANISMS OF AGE-RELATED COGNITIVE CHANGE AND TARGETS FOR INTERVENTION: EPIGENETICS

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


MECHANISMS OF AGE-RELATED COGNITIVE CHANGE AND TARGETS FOR INTERVENTION: EPIGENETICS

MADIHAH MOHAMAD, EIZZATI ARIPIN, SITI ZULAIHA ABU BAKAR


AGING AND EPIGENETIC

  • Changes- 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 II

  • U. 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 cortex

  • Memory 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 factor

  • Consolidation of memory = prevented by blocking the expression oh these genes

  • Normal 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 formation

  • Involving :

  • the covalent chemical modification of histones by histoneacetyltransferases and histonedeacetylases (HDACs)

  • covalent modification of DNA by DNA methyltransferases

  • Epigenetic 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 marks

  • transcription of key memory-promoting genes = decline during aging


  • An 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 signalling

  • Process :

  • 1st group of animals screened using spatial version of the Morris swim task = to confirm that the aged animals exhibited impaired memory

  • Animals explored (training) a novel environment for 5 mins (a week later) = treatment that results in both new memory formation

  • Animals rested in cage for 25 mins

  • Decapitation under deep isofluraneanesthesia

  • Extraction 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 DNA

  • 2nd 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 hippocampus

  • In 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 learning

  • Aging = 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 Aging


  • Biological aging:

    • Internal biological clock

    • Accumulation of insults to the organism

  • Lifespan of a species:

    • Biological aging

  • Life span of an individual:

    • Specific environmental circumstances (accumulated insults)

    • Individual differences of biological clock

  • These 2 facets operate at every level of biological hierarchy (genes, proteins, cells, organs, systems, organisms).


  • The 1st of relevant genetic pathways:

    • Discovered in 1993

    • Cynthia Kenyon found that a single gene mutation in daf-2 could double the lifespan of Caenorhabditiselegans

    • Could be reversed by a second mutation of daf-16m.

  • The following relevant genetic pathway:

    • Using the previous system

    • Discovered by Victor Ambrose

    • A novel class of posttranscriptional gene regulators called miRNAs.


  • Victor Ambrose’s discovery:

    • miRNAs form RNA-RNA duplex housed in RNA-induced silencing complex  partially silencing the translation of target mRNAs

    • A single miRNA targets multiple mRNAs

    • Recent findings suggest that their exquisite tissue specificity may open a door to the congnitive aging problem

    • Although several studies indicate that miRNA profiles change with age, the precise association of specific aging models is unclear

    • A coherent set of pathways related to aging will emerge

    • miRNA levels can be exogenously manipulated;

      • Upregulated – delivery of precursor miRNAs

      • Downregulated – delivery of locked nucleic acid antisense sequences


  • Sets of miRNA targets are often functionally related

  • Demonstrated 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 pathways

    • Shows 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 approach

  • The flaws in pharmaceutical approach:

    • Pathways are highly redundant

    • Inhibiting any single component  compensatory response

  • Identify & 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 target

    • Their depression  reduced level of specific miRNAs  accelerate an aging phenotype

    • e.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 differentiation

  • Biological aging begins the moment cells exit pluripotency

  • Pluripotency terminal differentiation can be tracked by a set of miRNA changes

  • Each discrete stage in a cell’s lineage is marked by a defining miRNA profile

  • Unraveling the complex target networks of miRNAs could offer important new insight into the aging process


Histone Acetylation and Histone Deacetylases in Mouse Models of Neurodegenration


  • Alzheimer’s disease (AD):

    • Age related neurodegenrative disorder associated with severe memory impairment

    • Prominent feature – the progressive loss of forebrain neurons and deterioration of learning and memory

    • No significantly effective treatment yet

    • The 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 sequence

    • e.g. chromatin remodeling – patterns of gene expression are modulated via the alteration of chromatin structure

    • Increased histone acetylation  more relaxed chromatin structure  increased gene expression

    • Histone 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 nucleus

    • Regulate histone acetylation + suppress gene expression

    • Recruited to the promoter regions of genes via transcriptional repressor and corepressor proteins

    • Recent studies – histone acetylation – learning and memory

    • Increased histone acetylation after various learning paradigms

    • After HDACi treatment, facilitation of synaptic plasticity and memory formation

    • Thus, increased histone acetylation facilitates cognitive function


  • CK-p25 mouse model experiment:

    • Nonselective HDACi sodium butyrate  improves cognitive performance (even after severe neurodegeneration)

    • HDACissuberoylanilidehydroxamic acid + phenylbutyrate  reinstate learning behaviour in AD mouse

    • They showed elevated H4 acetylation + increased production of proteins implicated in synaptic function

    • Treatment 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 affected

  • HDAC2 knockout mice (not HDAC1 knockout mice)  increased H4K12 and H4K5 acetylation + enhanced learning, memory, synaptic plasticity + rare model of cognitive enhancement


  • HDAC2:

    • Learning and memory

    • Synaptic plasticity

    • Regulation 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 suberoylanilidehydroxamic acid fails to further increase synaptic plasticity in HDAC2 knockout mice  HDAC2 appears to be the major target of HDACi in eliciting memory enhancement


  • Conclusion from the observations:

    • Dysregulation of chromatin remodeling cognitive impairment

    • Chronic 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 HistoneAcetylation The Molecular Link??


The Dentate Gyrus and Cognitive Aging

  • Frontal cortex and the hippocampal formation: strongly implicated in age-related memory decline

  • Hippocampal formation made up of:

    • Entorhinal cortex

    • Dentate gyrus

    • CA1 and CA3 pyramidal cell fields

    • subiculum


The Dentate Gyrus and Cognitive Aging


The Dentate Gyrus and Cognitive Aging


The Dentate Gyrus and Cognitive Aging

  • Each hippocampalsubregion expresses a unique malecular profile  this is why individual subregions are differentially vulnerable to disease

  • Age-related hippocampaldysf(x) due to:

    • Absence of neuron loss

    • Pathognomonic histological features


The Aging Dentate Gyrus and HistoneAcetylation

  • Histoneacetylation epigenetically regulates transcription

  • Dentate gyrus differentially engages this pathway

  • Unique feature of dentate gyrus is, it supports neurogenesis late into development, even into postnatal period

  • Histoneacetylation is a critical pathway for neuronal differentioation

  • Age- related defects in histoneacetylation play an important role in age-related dentate gyrusdysf(x)


The Aging Dentate Gyrus and HistoneAcetylation

  • Aging dentate gyrus age-related changes in molecules that regulate histoneacetylation

  • Therapeutic intervention:

    • Any interventions that ameliorate age-related hippocampaldysf(x), will improve the f(x) of dentate gyrus (via histoneacetylation pathway)

    • Physical excersice

    • Improving glucose control in DM


Concluding Comments

  • Cognitive aging is multifarious phenomenon

  • Key challenges:

    • To identify the precise epigenetic changes

    • To determine the time scale of their influence

    • To define how epigenetic mechanisms achieve specificity in the coordination of experience-dependent gene expression profile


  • Login