age & neuro-inflammation

8/14/2019 Age & Neuro-Inflammation

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Department ofDepartment of

PhysiologyPhysiology

Master of Science inMaster of Science in

PhysiologyPhysiology

SEMINAR IN PHYSIOLOGY:SEMINAR IN PHYSIOLOGY:

AGE & NEUROINFLAMMATION : AAGE & NEUROINFLAMMATION : A

LIFETIME OF PSYCHONEUROIMMUNELIFETIME OF PSYCHONEUROIMMUNECONSEQUENCES.CONSEQUENCES.


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DATA SOURCESDATA SOURCES

1.1. NEUROLOGIC CLINICSNEUROLOGIC CLINICS

VOLUME 24 (2006) pp. 521-548VOLUME 24 (2006) pp. 521-548

UP MANILA e-journal LIBRARYUP MANILA e-journal LIBRARY

AGE & NEUROINFLAMMATION : AAGE & NEUROINFLAMMATION : ALIFETIME OFLIFETIME OFPSYCHONEUROIMMUNEPSYCHONEUROIMMUNE

CONSEQUENCES.CONSEQUENCES. BY: JONATHAN P. GODBOUT, PhDBY: JONATHAN P. GODBOUT, PhD

RODNEY W. JOHNSON, PhDRODNEY W. JOHNSON, PhD


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TEXTBOOK REFERENCETEXTBOOK REFERENCE

2.2. Principles of NeurosciencePrinciples of Neuroscience

Chapter 58 : the aging brainChapter 58 : the aging brain

by Eric R. Kandelby Eric R. Kandel


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OBJECTIVESOBJECTIVES

1. DISCUSS THE MOLECULAR BASIS OF1. DISCUSS THE MOLECULAR BASIS OF

NEURAL AGING BRAINNEURAL AGING BRAIN

2. CONSEQUENCES OF GENETIC ABNORMALITIES OF2. CONSEQUENCES OF GENETIC ABNORMALITIES OF

APP GENE FOR THE FORMATION OF COGNITIVEAPP GENE FOR THE FORMATION OF COGNITIVE

DEFICITS & MEMORY LOSSDEFICITS & MEMORY LOSS3. DISCUSS THE RELATIONSHIP OF THE NEURAL3. DISCUSS THE RELATIONSHIP OF THE NEURAL

SYSTEM TO THE IMMUNE SYSTEM ONSYSTEM TO THE IMMUNE SYSTEM ONMICROGLIALMICROGLIAL

ACTIVATIVATION IN LIEU FOR INFLAMMATIONACTIVATIVATION IN LIEU FOR INFLAMMATION

4. DISCUSS THE EFECTS OF AGING ON THE4. DISCUSS THE EFECTS OF AGING ON THE

FUNCTION OF THE NEURAL SYSTEMFUNCTION OF THE NEURAL SYSTEM

5. SUGGESTED PREVENTION FOR LIMITING5. SUGGESTED PREVENTION FOR LIMITING

INFLAMMATION BY THE USE OF ANTI-OXIDANTSINFLAMMATION BY THE USE OF ANTI-OXIDANTS


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NORMAL DNA & SYNTHESISNORMAL DNA & SYNTHESIS


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MUTATIONS & DAMAGEMUTATIONS & DAMAGE


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AGING PROCESSAGING PROCESS

1.1. Senescence may result from the changes inSenescence may result from the changes ininformational macromolecules : DNA, RNA, &informational macromolecules : DNA, RNA, &Proteins)Proteins)

2.2. Mutations and chromosome anomaliesMutations and chromosome anomalies

accumulate as we undergo agingaccumulate as we undergo aging3.3. Errors in duplication of DNA occurs because ofErrors in duplication of DNA occurs because of

random damage occurs over time.random damage occurs over time.

4.4. Genetic errors accumulates, aberrant mRNA &Genetic errors accumulates, aberrant mRNA &

proteins are formed that leads to aging.proteins are formed that leads to aging.5.5. Specific genetic programs for aging alsoSpecific genetic programs for aging also

occursoccurs


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Aging (senescence) in humans causes general

deterioration in many tissues and systems

including loss of muscle mass, weakness,

reduced sensory acuity, reductions in nervous

system capabilities, reduced mobility, decline in

reproductive capacity, and various other

physiological changes.

Aging results in increased incidence and severity

of a wide variety of age-related diseases and

conditions, which, in developed countries, arethe cause of death for most people.


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CHANGES IN THE FUNCTION &CHANGES IN THE FUNCTION &

STRUCTURE OF THE BRAIN ARESTRUCTURE OF THE BRAIN ARE

ASSOCIATED WITH AGINGASSOCIATED WITH AGING

1.1. Many individuals as they aged show signs of aMany individuals as they aged show signs of a

decline in memory, & cognitive abilitiesdecline in memory, & cognitive abilities

(dementia)(dementia)

2.2. Behavioral changes like declining motor skills(Behavioral changes like declining motor skills(abnormalities in the PNS/CNS), sleep patternabnormalities in the PNS/CNS), sleep pattern

changes ( reduction in the stage 3 & stage 4changes ( reduction in the stage 3 & stage 4

time spent & REM , while the stage 1 slowtime spent & REM , while the stage 1 slow

wave sleep increases), posture changes,wave sleep increases), posture changes,

postural reflexes often sluggish that ispostural reflexes often sluggish that is

susceptible to loss in balance.susceptible to loss in balance.


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SENILE DEMENTIASENILE DEMENTIA

1.1. This refers to the clinical syndrome inThis refers to the clinical syndrome in

elderly that involves loss of memory &elderly that involves loss of memory &

cognitive impairments.cognitive impairments.

2.2. This can interfere with the social orThis can interfere with the social or

occupational functioning .occupational functioning .


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SENILE DEMENTIASENILE DEMENTIA

DSM-IV : shows 2 impairmentsDSM-IV : shows 2 impairments

a. memory loss but patient is alerta. memory loss but patient is alert

b. impairments in cognition ( language,b. impairments in cognition ( language,problem solving , judgement,problem solving , judgement,

calculation, attention, & perception)calculation, attention, & perception)


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GENETIC BASIS INCREASE RISKGENETIC BASIS INCREASE RISK

FOR ALZHEIMER DISEASEFOR ALZHEIMER DISEASE

1.1. APP GENE on Chromosome 21APP GENE on Chromosome 21

- the problem is mutation on the amino- the problem is mutation on the amino

acid substitutions flanking or within theacid substitutions flanking or within theAA region. ( Valine residue is replacedregion. ( Valine residue is replaced

by isoleucine, glycine or Phe position onby isoleucine, glycine or Phe position on

the positon 717)the positon 717)


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APP MUTATED POSITION 717APP MUTATED POSITION 717

There will be increased levels of AThere will be increased levels of A1-421-42

& A1-43.That has propensity to nucleate& A1-43.That has propensity to nucleate

rapidly into amyloid fibrils.rapidly into amyloid fibrils.


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2.2. Double mutation at residues 670 and 671Double mutation at residues 670 and 671

results in the substitution of Asn-Leu forresults in the substitution of Asn-Leu for

the normal Lys-Met.the normal Lys-Met.

- This abnormality can lead expressive- This abnormality can lead expressive

secretion of six to eight Asecretion of six to eight A peptide. peptide.

3.3. Mutation Glu to Gln substitution at Residue 693 (aminoMutation Glu to Gln substitution at Residue 693 (aminoacid 22 of A peptide)acid 22 of A peptide)

- This is associated to deposition of amyloid plaques in- This is associated to deposition of amyloid plaques in

the surrounding blood vessel walls.the surrounding blood vessel walls.


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4.4. Autosomal Dominant to Presenillin 1 geneAutosomal Dominant to Presenillin 1 gene

(Chromosome 14q)(Chromosome 14q)- the gene encodes for the 467 amino acid- the gene encodes for the 467 amino acid

polypeptide with eight transmembranepolypeptide with eight transmembrane

domains.domains.

- This Presenillin 1 accumulate in N-- This Presenillin 1 accumulate in N-

terminal (28 kDa fragment) and a C-terminal (28 kDa fragment) and a C-

Terminal (18 kDa fragment) that isTerminal (18 kDa fragment) that is

subject for endoproteolytic processing.subject for endoproteolytic processing.


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ALLELES GENES INCREASEALLELES GENES INCREASE

RISK OF ADRISK OF AD

1.1. ApoE: 34,000 molecular weight glycoproteinApoE: 34,000 molecular weight glycoproteinthat carries cholesterol & other lipids in thethat carries cholesterol & other lipids in theblood ( implicated for the late onset Alzheimerblood ( implicated for the late onset AlzheimerDisease)Disease)

2.2. 3 ALLELES of ApoE: ApoE2, ApoE3, and3 ALLELES of ApoE: ApoE2, ApoE3, andApoE4ApoE4

3.3. ApoE3: has cysteine at position 112 & arginineApoE3: has cysteine at position 112 & arginine

at position 158at position 1584.4. ApoE4: has both arginine on both positionApoE4: has both arginine on both position

5.5. ApoE2: has cystein at both positions.ApoE2: has cystein at both positions.


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ApoEApoE

1. ApoE isoforms influence the biology of A1. ApoE isoforms influence the biology of A

peptides.peptides.

AMYLOID DEPOSITS AREAMYLOID DEPOSITS ARE


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AMYLOID DEPOSITS AREAMYLOID DEPOSITS ARE

HALLMARKS OF ALZHEIMERHALLMARKS OF ALZHEIMER

DISEASEDISEASE1.1. AMYLOID PLAQUES (EXTRACELLULAR)AMYLOID PLAQUES (EXTRACELLULAR)

2.2. NEUROFIBRILLARY TANGLESNEUROFIBRILLARY TANGLES(INTRACELLULAR)(INTRACELLULAR)

3.3. INFLAMMATION (ASTROCYTES,INFLAMMATION (ASTROCYTES,MICROCYTOSIS, CYTOKINES COMPLEMENTMICROCYTOSIS, CYTOKINES COMPLEMENT& ACUTE PHASE INFLAMMATORY PROTEIN)& ACUTE PHASE INFLAMMATORY PROTEIN)

4.4. SELECTIVE NEURONAL DEGENERATIONSELECTIVE NEURONAL DEGENERATION5.5. SYNAPTIC LOSSSYNAPTIC LOSS

6.6. MULTIPLE NEUROTRANSMITTER DEFICITSMULTIPLE NEUROTRANSMITTER DEFICITS


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SENILE PLAQUESSENILE PLAQUES

- EXTRACELLULAR- EXTRACELLULARDEPOSITS OFDEPOSITS OFAMYLOID THATAMYLOID THATSURROUNDED BYSURROUNDED BYDYSTROPHICDYSTROPHICAXONS AS WELLAXONS AS WELLTHE PROCESSESTHE PROCESSESOF ASTROCYTES &OF ASTROCYTES &

MICROGLIAMICROGLIA(INFLAMMATORY(INFLAMMATORYCELLS).CELLS).


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AMYLOIDAMYLOID

1.1. Histological name for fibrillar peptidesHistological name for fibrillar peptides

that arranged in Beta pleated sheets inthat arranged in Beta pleated sheets in

aggregates that doubly refractive whenaggregates that doubly refractive when

stained with congo red.stained with congo red.

2.2. 4 kDa peptide called A4 kDa peptide called A amyloid is amyloid is

cleaved from a larger precursor proteincleaved from a larger precursor protein

amyloid precursor protein.amyloid precursor protein.


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HOW IS AHOW IS A AMYLOID CLEAVED? AMYLOID CLEAVED?

- Secretase cleaves- Secretase cleaves

APP at the N-APP at the N-

Terminus of the ATerminus of the A

peptide sequence inpeptide sequence inthe endosomalthe endosomal

compartment & thecompartment & the

gamma secretasegamma secretase

enzyme cleaves at theenzyme cleaves at theC terminus of AC terminus of A

peptide.peptide.


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THE IMMUNE RESPONSETHE IMMUNE RESPONSE


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IMMUNE CHANGESIMMUNE CHANGES This age-dependent impairment of immune function results from

weakened defenses by cells involved in innate and adaptiveimmunity.

Specifically there is a reduction in naive T cells, which are critical formounting both cell-mediated (T-cell) and humoral-mediated (B-cell)adaptive immune responses to novel antigens.

Immune dysfunction in the elderly is confounded further by adecrease in the production of anti-inflammatory hormones.

A consequence of these age-related impairments in the immune

and endocrine systems is a heightened proinflammatory profile in

the aged brain


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EIevated inflammatory profile has been detectedin aging brain with innate immune glia(astrocytes and microglia) displaying a more

reactive phenotype.

Recent findings indicate that a reactive gliapopulation sets the stage for an exaggerated

neuroinflammatory cytokine response afterperipheral innate immune activation.

The potential for reactive glia to mount an

exaggerated response to a secondary stimulusfrom the peripheral innate immune system isimportant for several reasons


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1. First, inflammatory cytokines in the brain

including interleukin (IL)-1b, IL-6, and tumor

necrosis factor alpha (TNF-a) are key mediators

of the sickness behavior syndrome.

Although transient brain exposure to

inflammatory cytokines is beneficial in the hostsinnate immune response , excessive or

prolonged exposure is associated with a myriad

of neurobehavioral complications including

cognitive dysfunction , anorexia, and mood and

depressive disorders


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1. Second, inflammatory cytokines are

involved in chronic neurodegenerative

diseases such as multiple sclerosis and

Alzheimers disease.

3. Finally, excessive or prolonged exposure

to inflammatory cytokines in the brain

abrogates neuronal plasticity, resulting in

behavioral and cognitive impairments.


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4. Therefore it is hypothesized that an

exacerbated neuroinflammatory cytokineresponse in the aged disrupts neuronal

synaptic plasticity, creating a brain

environment that is permissive to severe

long-lasting mental health complications.


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Fig. 1. Proposed mechanism of how aging exacerbatesneuroninflammation and neurobehavioral deficits when theperipheral innate immune system is activated. BBB, bloodbrainbarrier; IL, interleukin; TNF, tumor necrosis factor.


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THE RELATIONSHIP OF THETHE RELATIONSHIP OF THE

BRAIN & IMMUNE SYSTEMBRAIN & IMMUNE SYSTEMThe bidirectional communication between the immunesystem and brain is critical for mounting theappropriate immunologic, physiologic, and behavioralresponses to immune activation by infectiouspathogens.

The hosts first line of defense is the innate immunesystem. Innate immune cells are armed with pathogen-associated molecular pattern receptors, such as the

family of Toll-like receptors, which recognize specificpathogenic elements and elicit an immune response.


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This innate immune stimulation results in theproduction of inflammatory cytokines including

IL-1b, IL-6, and TNF-a by active peripheralmacrophages or monocytes.

These cytokines utilize both neural (by the

afferent vagus nerve) and humoral (bycircumventricular organs and direct transport )pathways to communicate this innate immunechallenge to the brain.


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This cytokine-mediated immune system

brain communication activates microglia,

the resident innate immune cells of the

brain, which induce and propagate thesesame cytokine signals throughout the

central nervous system.


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Critical for this immune systemCNS

interaction and the modulation of sickness

behavior are the resident innate immunecells of the brain.

Aside from neurons, macroglia and

microglia are the two primary cell types

located throughout the CNS.


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The macroglia are derived from a nerve cell

lineage and are classified into three distinct

subtypes: astrocytes, oligodendrocytes, andSchwann cells. These macroglia are the most

populous cells of the CNS and support and

maintain neuronal plasticity throughout the CNS.

Microglia also are interspersed throughout the

brain and represent approximately 10% of the

CNS population. Microglia differ from themacroglia because they are derived from a

monocyte/macrophage cell lineage.


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Microglia are pivotal in innate immune activation

and function to modulate neuroinflammatory

signals throughout the brain. In the absence ofstimulus, microglia are quiescent and have a

ramified morphology.

Active microglia show macrophage-like activities

including scavenging,phagocytosis, antigen

presentation, complement activation, and

inflammatory cytokine production.

Moreo er microglia recr it and acti ate


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Moreover microglia recruit and activateastrocytes to propagate these inflammatorysignals further.

Normally these neuroinflammatory changes aretransient, with microglia returning to a quiescentstate after the resolution of the immunechallenge.

Aging, however, may provide a brainenvironment in which microglia activation is notresolved, leading to a heightened sensitivity to

immune activation; this lack of resolution maycontribute to the pathogenesis of neurologicdisease.

E id f Alt d Gli


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Evidence of an Altered Glia

Population in the Aged Brain Age-associated alterations in immunity are

apparent in the innate immune cells of the brain.Recent evidence indicates there is an elevatedinflammatory profile in the aging brain consisting

of an increased population of reactive or primedglia.

Glial phenotypes of reactivity include increasedmicroglia expression of major histocompatibilitycomplexes (MHC), scavenger receptors, andcomplement receptors and increased astrocyte

expression of glial fibrillary protein (GFAP).


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In humans, alterations in microglia phenotype areespecially prevalent in patients who have inflammatorydisease or injury.

For example the MHC Class II marker in humans, HLA-DR, was detected in patients who have Alzheimersdisease and in older patients who have coronary artery

disease or spinal cord tract degeneration.

These alterations in the glia population were detected inhealthy, cognitively normal subjects as well, however.For instance, older individuals had increased IL-1apositive microglia with morphologic changes indicative ofenlarged or phagocytic microglia in the hippocampus.

E id f Alt d Gli


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Evidence of an Altered Glia

Population in the Aged Brain Age-associated alterations in immunity are

apparent in the innate immune cells of the brain.

Recent evidence indicates there is an elevated

inflammatory profile in the aging brain consistingof an increased population of reactive or primedglia.

Glial phenotypes of reactivity include increasedmicroglia expression of major histocompatibilitycomplexes


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(MHC), scavenger receptors, and

complement receptors and increased

astrocyteexpression of glial fibrillary

protein (GFAP).


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Microglial expression of MHC class II wasdetected in brains of aged but otherwise healthyhumans, on human primates, and rodents using

either immunohistochemical or mRNAmeasurements .

Microglial expression of complement receptor-3

and the macrosialin (CD68) scavenger receptoralso were elevated in the brain of aged rodents.Furthermore, the expression of GFAP, a markerof astrogliosis, was increased in several of thesesame rodent models of aging.


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It is noteworthy that the actual number of residentastrocytes and microglia did not increase in the brainwith age .

Therefore the expression of markers indicative of glialreactivity seems to be increased in existing astrocytesand microglia populations.

There is, however, evidence of sex-dependentandregion-specific glia increases with age.

The active and reactive glia have a similar morphology(ie, deramified), reactive glia do not produce appreciable

levels of proinflammatory cytokines in this state.

Immune Consequences of Reactive


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Immune Consequences of Reactive

Glia in the Aged Brain A potential consequence of a reactive glial cell population in the

brain is an exaggerated inflammatory response to innate immuneactivation.

Perry and colleagues at the University of Southampton, UnitedKingdom, have proposed that systemic infection exacerbates the

progression of neurodegenerative disease.

In this circumstance the brain environment created by theneurologic disease provides a primary trigger for microglia reactivity,and peripheral infection provides the secondary stimulus.

In the ME-7 murine model of prion disease, microglia are activatedthroughout the limbic system, including the hippocampus whereneuron loss occurs.


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In this circumstance the brain environmentcreated by the neurologic disease provides aprimary trigger for microglia reactivity, andperipheral infection provides the secondary

stimulus.

In the ME-7 murine model of prion disease,microglia are activated throughout the limbicsystem, including the hippocampus whereneuron loss occurs.


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Furthermore, deposition of b amyloidwithin senile plaques is a classic feature of

Alzheimers disease, and conditionsleading to the expression of inflammatorycytokines in brain are associated with theinduction of b amyloid precursor protein.

In the Tg2576 murinemodel of Alzheimersdisease, intravenous injection of LPS

caused agedependent increases in brainIL-1b and TNF-a levels and increasedamyloid deposition.


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This deposition may promote

neuroinflammationfurther, because b

amyloid activates microglia. Collectively

these data indicate that innate immuneactivation contributes both to the

pathogenesis of neurodegenerative

disease and to the severity of theassociated neurobehavioral complications.


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Hypersensitivity to innate immuneactivation in the brain also is evident in

several animal models of aging.

The primary mixed glia cultures and

coronal brain sections established fromthe brain of aged rodents were hyper-responsive to LPS stimulation andproduced more inflammatory cytokines(IL-1b and IL-6) than cultures establishedfrom adult brains.

In a murine model of aging older mice were


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In a murine model of aging, older mice weremore sensitive to septic shock induced byintracerebroventricular (ICV) administration of

LPS.

Older mice had elevated TNF-a production in thebrain and plasma after LPS challenge compared

with adult controls.

In another murine model of aging, microarrayanalysis revealed that peripheral injection of LPSinduced a higher expression of IL-1b and TNF-ain the hippocampus of aged mice than in adults.


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Innate immune system with LPS caused an exaggeratedinflammatory cytokine response in the aged brain withincreased production of IL-6 and IL-1b. Furthermore,

aged mice that experienced a LPS-induced amplifiedand prolonged neuroinflammatory response showed adelayed recovery from sickness behavior.

Finally, in a rat model of aging, in which increased

reactive glia with MHC class II expression were detected,peripheral injection of Escherichia coli promoted higherlevels of IL-1b in the hippocampus of aged rats than inadults.

This increased IL-1b production in the hippocampus ofaged rats after E coli challenge was associated withimpaired long-term hippocampal dependent memory.

Are Neurobehavioral Complications a


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Are Neurobehavioral Complications a

Consequence of Prolonged Exposure of

Proinflammatory Cytokines?

Recent experimental evidence suggests that an amplified andprolonged inflammatory response in the aged brain promotesprotracted behavioral and cognitive impairments.

These findings seem to be supported by clinical evidence indicatingthat many of the behavioral consequences of illness and infection in

the elderly, if prolonged, can have deleterious affects on mentalhealth.

For example, there is an increased prevalence of delirium in elderlyemergency department patients as a result of infections unrelated tothe CNS.


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The most striking characteristic of pneumonia (eitherviral or bacterial) in the aged is that it frequently

presents clinically as delirium, even in the absence ofclassic pneumonia symptoms.

A clinical study showed that 34% of elderly patients

diagnosed with delirium had an infection.

A follow-up of these patients 1 year later revealedincreased rates of mortality, institutionalization, andhospital readmittance.

Furthermore, delirium is a risk factor for progression intodementia.

Does Heightened Inflammatory Cytokine Exposure


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Does Heightened Inflammatory Cytokine Exposure

Impair Neuronal Plasticity

and Cause Neurobehavioral Complications?

Inflammatory cytokines provokebehavioral responses, in part, bymodulating neuronal activity.

Synaptic plasticity encompasses a numberofimportant brain functions that maintaincognitive and behavioral homeostasisincluding long-term potentiation (LTP),neurogenesis, and neuriteoutgrowth.


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GLIA CELLSGLIA CELLS


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Neuronal plasticity is essential in brain areas associatedwith modulating cognition and behavior, such as thehippocampus.

The hippocampus and the hypothalamus have thehighest expression of inflammatory cytokine receptorsfor IL-1b and IL-6. In some instances inflammatorycytokine exposure leads to neuronal cell death,

especially in neurologic disease, endotoxic shock, orchronic inflammatory conditions, but normalneuroinflammatory responses that mediatesicknessbehavior do not.

In fact, in primary or transformed cultures cytokines suchas IL-6 and IL-1b have growth-promoting effects onneurons and may play a role in early brain development.


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Inflammatory cytokines also can impair

neurite outgrowth, a critical process

involved in modifying existing synapticconnections.

For example, in primary hippocampalneurons cultured on astrocytes, IL-1b

stimulated astrocytes to produce TNF-a,

which inhibited the neurite outgrowth and Branching.

How Do Glia Become More


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How Do Glia Become More

Reactive With Age?

There are several plausible explanations forincreased glia sensitivity with age.

1. Inflammatory cytokine exposure over a

course of a lifespan increases the number ofreactive glia in the brain.

A recent longitudinal study from Swedendemonstrated that young individuals exposed toinflammatory events early in life had a higherorbidity and mortality rate as they aged.

2 LPS caused a significant increase in astrocyte


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2. LPS caused a significant increase in astrocyteexpression of GFAP in the CA3 region of thehippocampus in rats infected as neonates .

The astrocyte reactivity to secondary challenge of LPSin adulthood was associated with a severe deficit inhippocampal dependent

memory.

Although the IL-1b cytokine response was unchanged inthe hippocampus, increased astrocyte expression ofGFAP was

interpreted as suggesting an exaggerated

neuroinflammatory response.

Reactive glia also may be derived by inflammatoryprocess later in life.

Limiting Inflammatory Exposure


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Limiting Inflammatory Exposure

With Antioxidants The induction of sickness behavior is a necessary and

important response to systemic infection .

Instances when sickness behavior is too severe or

prolonged, however, may cause long-lasting behavioraland cognitive impairments .

The developing interventions that limit thisneuroinflammatory process without affecting induction ofthe response is of particular interest. One potentialcytokine target could be IL-6.

IL 6 l d t i d i k


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IL-6 exposure alone does not induce sicknessbehavior , in combination with other cytokines ithas an important role in the maintenance of

sickness behavior.

This notion is supported by evidence that IL-6knockout mice recovered faster from LPS-

induced sickness , and protracted IL-6expression in the brain of aged mice waspositively correlated with prolonged sicknessbehavior.

Moreover, the antioxidant a-tocopherol (vitaminE) attenuates the inflammatory responseinduced by LPS by reducing lipid.

THANK YOUTHANK YOU


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THANK YOUTHANK YOU

age & neuro-inflammation

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