1. Today Feb 27…  Apoptosis  Aging of the Nervous System  Apoptosis  Aging of the Nervous System

2. APOPTOSIS What is it? Why is it important? How is it controlled? What is its role in age-related disease?

3. APOPTOSIS Programmed cell death Orderly cellular self destruction Process: as crucial for survival of multi-cellular organisms as cell division MULTIPLE FORMS???

4. 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

5. 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

6. APOPTOSIS: important in embryogenesis Morphogenesis (eliminates excess cells): Selection (eliminates non-functional cells):

7. APOPTOSIS: important in embryogenesis Immunity (eliminates dangerous cells): Self antigen recognizing cell Organ size (eliminates excess cells):

8. APOPTOSIS: important in adults Tissue remodeling (eliminates cells no longer needed): Virgin mammary gland Late pregnancy, lactation Involution (non-pregnant, non-lactating) Apoptosis - Testosterone Prostate gland

9. 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

10. 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 cells restricts how many times this can occur before tissue renewal declines) X

11. APOPTOSIS: control Receptor pathway (physiological): Death receptors: (FAS, TNF-R, etc) FAS ligand TNF Death domains Adaptor proteins Pro-caspase 8 (inactive)Caspase 8 (active) Pro-execution caspase (inactive) Execution caspase (active) Death MITOCHONDRIA

12. 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 BAX BAK BOK BCL-Xs BAD BID B IK BIM NIP3 BNIP3 BCL-2 BCL-XL BCL-W MCL1 BFL1 DIVA NR-13 Several viral proteins

13. APOPTOSIS: control Physiological Intrinsic receptor pathway damage pathway MITOCHONDRIAL SIGNALS Caspase cleavage cascade Orderly cleavage of proteins and DNA CROSSLINKING OF CELL CORPSES; ENGULFMENT (no inflammation)

14. APOPTOSIS: Role in Disease TOO MUCH: Tissue atrophy TOO LITTLE: Hyperplasia Neurodegeneration Thin skin etc Cancer Athersclerosis etc

15. 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.

16. 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

17. 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)

18. OPTIMAL FUNCTION (HEALTH) APOPTOSIS AGING Neurodegeneration, cancer, …..

19. 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?  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?

20. Aging of the Nervous System: Structural Changes

21. 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.  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.

22. 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  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

23. Regenerative potential depends on changes in whole body and neural microenvironment  Whole body changes:  Physical exercise  Appropriate nutrition  Good circulation  Education  Stress  others  Whole body changes:  Physical exercise  Appropriate nutrition  Good circulation  Education  Stress  others Neural microenvironment Neural microenvironment changes: changes: –Brain metabolism (oxygen consumption, free radicals, circulatory changes) –Hormonal changes (estrogens, growth factors, others) –others

24. 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

25. Aging of the Nervous System  Structural Changes 1.Changes in Brain Weight 2.Denudation 3.Loss of Neurons 4.Neuropatholog ical Markers  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

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

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

28. 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) 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)

29. 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  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

30. Fig. 7-5: Free radical accumulation (lipofuscin) in young rats and old rats Fig. 7-6: Neuron from 605 day old rat Fig. 7-7: Magnification of lipofuscin granules of Fig. 7-6 Young Old

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

32. 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

33. 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)  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)

34. 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?  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?