Today Feb 27… Apoptosis Aging of the Nervous System Apoptosis Aging of the Nervous System.
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Transcript of Today Feb 27… Apoptosis Aging of the Nervous System Apoptosis Aging of the Nervous System.
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?