Download APOPTOSIS

Today Feb 27…
 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-cellular
organisms as cell division
MULTIPLE FORMS???
Forms of cell death
Necrosis
Passive
Pathological
Swelling, lysis
"Classic"
Apoptosis
Active
Physiological or
pathological
Condensation,
cross-linking
Mitotic catastrophe
Passive
Pathological
Swelling, lysis
Dissipates
Phagocytosed
Dissipates
Inflammation
No inflammation
Inflammation
Externally induced
Internally or
externally induced
Internally 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 antigen
recognizing cell
Organ size (eliminates excess cells):
APOPTOSIS: important in adults
Tissue remodeling (eliminates cells no longer needed):
Apoptosis
Virgin mammary gland
Late pregnancy, lactation
- Testosterone
Apoptosis
Prostate gland
Involution
(non-pregnant, non-lactating)
APOPTOSIS: important in adults
Tissue remodeling (eliminates cells no longer needed):
Apoptosis
Resting lymphocytes
+ antigen (e.g. infection)
- antigen (e.g. recovery)
Steroid immunosuppressants: kill
lymphocytes by apoptosis
Lymphocytes poised to die by apoptosis
APOPTOSIS: important in adults
Maintains organ size and function:
Apoptosis
X
+ cell division
Cells lost by apoptosis are replaced by cell division
(remember limited replicative potential of normal cells
restricts how many times this can occur before
tissue renewal declines)
APOPTOSIS: control
Receptor pathway (physiological):
FAS ligand
Death receptors:
(FAS, TNF-R, etc)
TNF
Death
domains
Adaptor proteins
Pro-caspase 8 (inactive)
Pro-execution caspase (inactive)
MITOCHONDRIA
Caspase 8 (active)
Execution caspase (active)
Death
APOPTOSIS: control
Intrinsic pathway (damage):
Mitochondria
BAX
BAK
BOK
BCL-Xs
BAD
BID
B IK
BIM
NIP3
BNIP3
Cytochrome c release
Pro-caspase 9 cleavage
Pro-execution caspase (3) cleavage
BCL-2
BCL-XL
BCL-W
MCL1
BFL1
DIVA
NR-13
Several
viral
proteins
Caspase (3) cleavage of cellular proteins,
nuclease activation,
etc.
Death
APOPTOSIS: control
Physiological
receptor pathway
Intrinsic
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
Neurodegeneration
Thin skin
etc
TOO LITTLE: Hyperplasia
Cancer
Athersclerosis
etc
APOPTOSIS: Role in Disease
Neurodegeneration
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 DISEASE
ALZHEIMER'S DISEASE
HUNTINGTON'S DISEASE etc.
APOPTOSIS: Role in Disease
Cancer
Apoptosis eliminates damaged cells
(damage => mutations => cancer
Tumor suppressor p53 controls senescence
and apoptosis responses to damage
Most cancer cells are defective in apoptotic response
(damaged, mutant cells survive)
High levels of anti-apoptotic proteins
or
Low levels of pro-apoptotic proteins
===> CANCER
APOPTOSIS: Role in Disease
AGING
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 accumulate
hyperplasia (precancerous lesions)
OPTIMAL FUNCTION (HEALTH)
APOPTOSIS
AGING
APOPTOSIS
Neurodegeneration, cancer, …..
Questions
 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
System:
Structural Changes
Brain Plasticity and
CNS Regenerative Potential (A review of 2
previous lectures given)
 From the beginning of the 20th Century until the
1990s, it was stated that neurons DID NOT
proliferate.
 The fact that they COULD NOT proliferate did not
exclude the possibility of proliferation under
“specific conditions.”
 In fact, the CNS has a considerable regenerative
potential depending on the special conditions of
the neuronal environment.
Neurons that may proliferate into
adulthood include:
 Progenitor “precursor” neurons lining the
cerebral ventricules
 Neurons in the hippocampus
 Neurons usually “dormant” with potential for
neuron and glia proliferation
 Neuroglia (astrocytes, oligodentrocytes) and
microglia (immune cells) with the ability to
perpetually self renew and produce the three
types of neural cells
Regenerative potential depends on
changes in whole body and neural
microenvironment
 Whole body
changes:
 Physical exercise
 Appropriate
nutrition
 Good circulation
 Education
 Stress
 others
• Neural
microenvironment
changes:
–Brain metabolism
(oxygen consumption,
free radicals,
circulatory changes)
–Hormonal changes
(estrogens, growth
factors, others)
–others
Major Function of the Nervous
System
The major function of the CNS is to
communicate & to connect:
with other CNS cells
with peripheral tissues (outside CNS)
with the external environment (including
physical and social environments)
This communication regulates:
Mobility
Sensory information
Cognition
Affect and mood
Functions of whole-body systems
Aging of the Nervous
System

Structural
Changes
1. Changes in
Brain Weight
2. Denudation
3. Loss of
Neurons
4. Neuropatholog
ical Markers

Biochemical
Changes (will
be in a lecture
YET TO COME)
1. Neurotransmitt
ers
2. CNS Synapses
3. Neurotransmitt
er Imbalance
and Brain
Disorders
Fig. 7-2: Changes in
brain weight with
aging in human
males and females
Fig. 7-4: “Denudation” of the neurons. Changes in
pyramidal neurons of the aging human cerebral cortex
In normal aging, the loss of
neurons is moderate & occurs in
specific brain areas:
 Locus ceruleus (catecholaminergic
neurons)
 Substantia nigra (dopaminergic
neurons)
 Nucleus basalis of Meynert
(cholinergic neurons)
 Hippocampus (cholinergic neurons)
Neuropathologies
 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
Young
Fig. 7-6: Neuron
from 605 day old
rat
Old
Fig. 7-5: Free radical accumulation
(lipofuscin) in young rats and old rats
Fig. 7-7:
Magnification of
lipofuscin
granules of Fig.
7-6
Fig. 7-8: Lewy Bodies. Aggregation of filaments,
vesicular profiles and poorly resolved granular
material
C
A & B: Fibrillary tangles
Alterations of tau
protein and microtubule
assembly? Paired Helical
Filaments (PHF)
C: Neuritic plaque
Accumulation of amyloid
broken down PHFs
Pathological and Cellular
Changes with Normal Aging
 Increased intracellular deposits of
lipofuscin
 Intracellular formation of PHFs
 Accumulation of amyloid deposits in
the neuritic plaques and
surrounding the cerebral blood
vessels
 Accumulation of Lewy bodies
 Cell death (apoptosis, necrosis)
Questions
 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?