Today Feb 27…Today Feb 27…

Apoptosis Aging of the Nervous System

Apoptosis Aging of the Nervous System

APOPTOSIS

What is it?

Why is it important?

How is it controlled?

What is its role in age-related disease?

APOPTOSIS

Programmed cell death

Orderly cellular self destruction

Process: as crucial for survival of multi-cellularorganisms as cell division

MULTIPLE FORMS???

Forms of cell death

"Classic"Necrosis Apoptosis Mitotic catastrophe

Passive Active Passive

Pathological Physiological or Pathological pathological

Swelling, lysis Condensation, Swelling, lysis cross-linking

Dissipates Phagocytosed Dissipates

Inflammation No inflammation Inflammation

Externally induced Internally or Internally induced externally induced

STAGES OF CLASSIC APOPTOSIS

Healthy cell

DEATH SIGNAL (extrinsic or intrinsic)

Commitment to die (reversible)

EXECUTION (irreversible)

Dead cell (condensed, crosslinked)

ENGULFMENT (macrophages, neighboring cells)

DEGRADATION

APOPTOSIS: important in embryogenesis

Morphogenesis (eliminates excess cells):

Selection (eliminates non-functional cells):

APOPTOSIS: important in embryogenesis

Immunity (eliminates dangerous cells):

Self antigenrecognizing cell

Organ size (eliminates excess cells):

APOPTOSIS: important in adults

Tissue remodeling (eliminates cells no longer needed):

Virgin mammary gland Late pregnancy, lactation Involution(non-pregnant, non-lactating)

Apoptosis

Apoptosis

- Testosterone

Prostate gland

APOPTOSIS: important in adults

Tissue remodeling (eliminates cells no longer needed):

Resting lymphocytes + antigen (e.g. infection) - antigen (e.g. recovery)

Apoptosis

Steroid immunosuppressants: kill lymphocytes by apoptosis

Lymphocytes poised to die by apoptosis

APOPTOSIS: important in adults

Maintains organ size and function:

Apoptosis+ cell division

Cells lost by apoptosis are replaced by cell division

(remember limited replicative potential of normal cellsrestricts how many times this can occur before

tissue renewal declines)

X

APOPTOSIS: control

Receptor pathway (physiological):

Death receptors:(FAS, TNF-R, etc)

FAS ligand TNF

Deathdomains

Adaptor proteins

Pro-caspase 8 (inactive) Caspase 8 (active)

Pro-execution caspase (inactive)Execution caspase (active)

DeathMITOCHONDRIA

APOPTOSIS: control

Intrinsic pathway (damage):

Mitochondria

Cytochrome c release

Pro-caspase 9 cleavage

Pro-execution caspase (3) cleavage

Caspase (3) cleavage of cellular proteins,nuclease activation,

etc.

Death

BAXBAKBOKBCL-XsBADBIDB IKBIMNIP3BNIP3

BCL-2BCL-XLBCL-WMCL1BFL1DIVANR-13Several viral proteins

APOPTOSIS: control

Physiological Intrinsicreceptor pathway damage pathway

MITOCHONDRIAL SIGNALS

Caspase cleavage cascade

Orderly cleavage of proteins and DNA

CROSSLINKING OF CELL CORPSES; ENGULFMENT(no inflammation)

APOPTOSIS: Role in Disease

TOO MUCH: Tissue atrophy

TOO LITTLE: Hyperplasia

NeurodegenerationThin skin

etc

CancerAthersclerosis

etc

APOPTOSIS: Role in DiseaseNeurodegeneration

Neurons are post-mitotic (cannot replace themselves;neuronal stem cell replacement is inefficient)

Neuronal death caused by loss of proper connections,loss of proper growth factors (e.g. NGF), and/or

damage (especially oxidative damage)

Neuronal dysfunction or damage results in loss of synapses or loss of cell bodies

(synaptosis, can be reversible; apopsosis, irreversible)

PARKINSON'S DISEASEALZHEIMER'S DISEASE

HUNTINGTON'S DISEASE etc.

APOPTOSIS: Role in DiseaseCancer

Apoptosis eliminates damaged cells(damage => mutations => cancer

Tumor suppressor p53 controls senescenceand apoptosis responses to damage

Most cancer cells are defective in apoptotic response(damaged, mutant cells survive)

High levels of anti-apoptotic proteinsor

Low levels of pro-apoptotic proteins===> CANCER

APOPTOSIS: Role in DiseaseAGING

Aging --> both too much and too little apoptosis(evidence for both)

Too much (accumulated oxidative damage?)---> tissue degeneration

Too little (defective sensors, signals?---> dysfunctional cells accumulatehyperplasia (precancerous lesions)

OPTIMAL FUNCTION (HEALTH)

APOPTOSIS

APOPTOSIS

AGING

Neurodegeneration, cancer, …..

QuestionsQuestions

Why is apoptosis important embryologically?

Why is apoptosis important in adults? What can too much apoptosis cause? Too little apoptosis? What is the difference between

apoptosis and necrosis?

Why is apoptosis important embryologically?

Why is apoptosis important in adults? What can too much apoptosis cause? Too little apoptosis? What is the difference between

apoptosis and necrosis?

Aging of the Nervous Aging of the Nervous System:System:

Structural ChangesStructural Changes

Brain Plasticity and Brain Plasticity and CNS Regenerative Potential (A review of 2 CNS Regenerative Potential (A review of 2

previous lectures given)previous lectures given)

Brain Plasticity and Brain Plasticity and CNS Regenerative Potential (A review of 2 CNS Regenerative Potential (A review of 2

previous lectures given)previous lectures given)

From the beginning of the 20th Century until the 1990s, From the beginning of the 20th Century until the 1990s, it was stated that neurons DID NOT proliferate.it was stated that neurons DID NOT proliferate.

The fact that they COULD NOT proliferate did not The fact that they COULD NOT proliferate did not exclude the exclude the possibilitypossibility of proliferation under “specific of proliferation under “specific conditions.”conditions.”

In fact, the CNS has a considerable regenerative In fact, the CNS has a considerable regenerative potential depending on the special conditions of the potential depending on the special conditions of the neuronal environment.neuronal environment.

Neurons that may proliferate into Neurons that may proliferate into adulthood include:adulthood include:

Neurons that may proliferate into Neurons that may proliferate into adulthood include:adulthood include:

Progenitor “precursor” neurons lining the cerebral Progenitor “precursor” neurons lining the cerebral ventriculesventricules

Neurons in the hippocampusNeurons in the hippocampus Neurons usually “dormant” with potential for Neurons usually “dormant” with potential for

neuron and glia proliferationneuron and glia proliferation Neuroglia (astrocytes, oligodentrocytes) and Neuroglia (astrocytes, oligodentrocytes) and

microglia (immune cells) with the ability to microglia (immune cells) with the ability to perpetually self renew and produce the three types perpetually self renew and produce the three types of neural cellsof neural cells

Regenerative potential depends on Regenerative potential depends on changes in changes in whole body whole body and and neural neural

microenvironmentmicroenvironment

Whole body changes:Whole body changes: Physical exercisePhysical exercise Appropriate Appropriate

nutritionnutrition Good circulationGood circulation EducationEducation StressStress othersothers

• Neural Neural microenvironment microenvironment changes:changes:

–Brain metabolism Brain metabolism (oxygen consumption, (oxygen consumption, free radicals, circulatory free radicals, circulatory changes)changes)–Hormonal changes Hormonal changes (estrogens, growth (estrogens, growth factors, others)factors, others)–othersothers

Major Function of the Nervous SystemMajor Function of the Nervous System

The major function of the CNS is to The major function of the CNS is to communicate & to connect:communicate & to connect:

with other CNS cellswith other CNS cellswith peripheral tissues (outside CNS)with peripheral tissues (outside CNS)

with the external environment (including physical with the external environment (including physical and social environments)and social environments)

This communication regulates:This communication regulates:MobilityMobility

Sensory informationSensory informationCognition Cognition

Affect and moodAffect and moodFunctions of whole-body systemsFunctions of whole-body systems

Aging of the Nervous System

Aging of the Nervous System

Structural Changes1. Changes in Brain

Weight2. Denudation3. Loss of Neurons4. Neuropathologica

l Markers

Structural Changes1. Changes in Brain

Weight2. Denudation3. Loss of Neurons4. Neuropathologica

l Markers

Biochemical Changes (will be in a lecture YET TO COME)1. Neurotransmitter

s2. CNS Synapses3. Neurotransmitter

Imbalance and Brain Disorders

Biochemical Changes (will be in a lecture YET TO COME)1. Neurotransmitter

s2. CNS Synapses3. Neurotransmitter

Imbalance and Brain Disorders

Fig. 7-2Fig. 7-2: Changes in : Changes in brain weight with brain weight with aging in human aging in human males and femalesmales and females

Fig. 7-4Fig. 7-4: “Denudation” of the neurons. Changes in : “Denudation” of the neurons. Changes in pyramidal neurons of the aging human cerebral cortexpyramidal neurons of the aging human cerebral cortex

In normal aging, the loss of neurons In normal aging, the loss of neurons is moderate & occurs in specific is moderate & occurs in specific brain areas:brain areas:

Locus ceruleus (catecholaminergic Locus ceruleus (catecholaminergic neurons)neurons)

Substantia nigra (dopaminergic Substantia nigra (dopaminergic neurons)neurons)

Nucleus basalis of Meynert (cholinergic Nucleus basalis of Meynert (cholinergic neurons) neurons)

Hippocampus (cholinergic neurons) Hippocampus (cholinergic neurons)

In normal aging, the loss of neurons In normal aging, the loss of neurons is moderate & occurs in specific is moderate & occurs in specific brain areas:brain areas:

Locus ceruleus (catecholaminergic Locus ceruleus (catecholaminergic neurons)neurons)

Substantia nigra (dopaminergic Substantia nigra (dopaminergic neurons)neurons)

Nucleus basalis of Meynert (cholinergic Nucleus basalis of Meynert (cholinergic neurons) neurons)

Hippocampus (cholinergic neurons) Hippocampus (cholinergic neurons)

NeuropathologiesNeuropathologies Lipofuscin

By-product of cellular autophagia Linear increase with normal aging Function in disease unkown

Lewy Bodies Present in normal aging (60+) Increased accumulation in Parkinson’s Disease

Neurofibrillary Tangles Tangled masses of fibrous elements Present in normal aging in hippocampus Accumulation in cortex is sign of Alzheimer’s

Lipofuscin By-product of cellular autophagia Linear increase with normal aging Function in disease unkown

Lewy Bodies Present in normal aging (60+) Increased accumulation in Parkinson’s Disease

Neurofibrillary Tangles Tangled masses of fibrous elements Present in normal aging in hippocampus Accumulation in cortex is sign of Alzheimer’s

Fig. 7-5Fig. 7-5: Free radical accumulation : Free radical accumulation ((lipofuscin)lipofuscin) in young rats and old rats in young rats and old rats

Fig. 7-6Fig. 7-6: Neuron : Neuron from 605 day old from 605 day old ratrat

Fig. 7-7Fig. 7-7: : Magnification of Magnification of lipofuscin granules lipofuscin granules of Fig. 7-6of Fig. 7-6

YounYoungg

OldOld

Fig. 7-8Fig. 7-8: Lewy Bodies. Aggregation of filaments, : Lewy Bodies. Aggregation of filaments, vesicular profiles and poorly resolved granular vesicular profiles and poorly resolved granular

materialmaterial

C

A & BA & B: Fibrillary tangles: Fibrillary tanglesAlterations of tau protein Alterations of tau protein and microtubule assembly? and microtubule assembly? Paired Helical Filaments Paired Helical Filaments (PHF)(PHF)

CC: Neuritic plaque: Neuritic plaqueAccumulation of amyloid Accumulation of amyloid broken down PHFsbroken down PHFs

Pathological and Cellular Pathological and Cellular Changes with Normal AgingChanges with Normal Aging

Pathological and Cellular Pathological and Cellular Changes with Normal AgingChanges with Normal Aging

Increased intracellular deposits of Increased intracellular deposits of lipofuscinlipofuscin

Intracellular formation of PHFsIntracellular formation of PHFs Accumulation of amyloid deposits in the Accumulation of amyloid deposits in the

neuritic plaques and surrounding the neuritic plaques and surrounding the cerebral blood vesselscerebral blood vessels

Accumulation of Lewy bodiesAccumulation of Lewy bodies Cell death (apoptosis, necrosis)Cell death (apoptosis, necrosis)

Increased intracellular deposits of Increased intracellular deposits of lipofuscinlipofuscin

Intracellular formation of PHFsIntracellular formation of PHFs Accumulation of amyloid deposits in the Accumulation of amyloid deposits in the

neuritic plaques and surrounding the neuritic plaques and surrounding the cerebral blood vesselscerebral blood vessels

Accumulation of Lewy bodiesAccumulation of Lewy bodies Cell death (apoptosis, necrosis)Cell death (apoptosis, necrosis)

QuestionsQuestions

What are the pathological/cellular changes that occur with normal aging?

What are the normal structural changes with aging?

What are some examples of the areas of the brain where there is loss of neurons?

What conditions favor neuroregeneration?

What are the pathological/cellular changes that occur with normal aging?

What are the normal structural changes with aging?

What are some examples of the areas of the brain where there is loss of neurons?

What conditions favor neuroregeneration?