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Apoptosis and neurological disorders

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Dr. Parag Moon Senior resident Dept. of Neurology GMC Kota.
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Page 1: Apoptosis and neurological disorders

Dr. Parag MoonSenior resident

Dept. of NeurologyGMC Kota.

Page 2: Apoptosis and neurological disorders

1.Necrosis

Follows acute ischemia or traumatic injury.

Occurs in most severely affected areas

Abrupt biochemical collapse lead to generation of free radicals, excitotoxins.

Mitochondrial & nuclear swelling, dissolution of organelles, condensation of chromatin around nucleus.

Rupture of nuclear and cytoplasmic membranes and degradation of DNA.

Extremely difficult to treat or prevent.

Page 3: Apoptosis and neurological disorders

2.Apoptosis Programmed cell death Seen in both acute and chronic neurologic

diseases. After acute insults occurs in areas that are

not severely affected by injury. Apoptosis occurs in penumbra, where

collateral blood flow reduces degree of hypoxia.

Chronic neurodegenerative diseases it is predominant form of cell death

Page 4: Apoptosis and neurological disorders

Biochemical cascade activates proteases that destroy molecules that are required for cell survival.

Cytoplasm condenses, mitochondria and ribosomes aggregate, nucleus condenses & chromatin aggregates.

Cell fragments into “apoptotic bodies”

Page 5: Apoptosis and neurological disorders

Chromosomal DNA is enzymatically cleaved to 180-bp internucleosomal fragments.

Reduction in membrane potential of mitochondria

Intracellular acidification

Generation of free radicals

Externalization of phosphatidylserineresidues

Page 6: Apoptosis and neurological disorders

Death by Injury vs. Death by Suicide

(Necrosis vs. Apoptosis)

Page 7: Apoptosis and neurological disorders

Caspases

Cysteine-dependent, aspartate-specific proteases.

Homologous to nematode ced-3 gene product

So far 14 members of caspase family have been identified, 11 of which present in humans.

Page 8: Apoptosis and neurological disorders

Exist as latent precursors.

Procaspases are composed of p10 and p20 subunits and an N-terminal recruitment domain.

Active caspases are heterotetramersconsisting of two p10 and two p20 subunits derived from two procaspase molecules

Have been categorized into upstream initiators and downstream executioners

Page 9: Apoptosis and neurological disorders

Upstream caspases are activated by cell-death signal (e.g.TNFa)

Have a long N-terminal prodomain that regulates their activation.

Upstream caspases activate downstream caspases, which directly mediate events leading to demise of cell.

Downstream caspases have short N-terminal prodomain.

Page 10: Apoptosis and neurological disorders

Upstream caspases subclassified into two groups according to molecules modulating their activation.

Procaspases 1,2,4,5,9,11,12,13 have long N-terminal prodomain called caspase-recruiting domain (CARD).

Caspases 8 and 10 have long N-terminal prodomain called death-effector domain (DED).

Page 11: Apoptosis and neurological disorders

Caspases 2,8,9,10-initiators of apoptosis-with a long prodomain

Caspases 1,4,5,11,12,13-cytokine activation

Caspases 3,6,7-effectors of apoptosis

Caspase 14-cytokine maturation

Page 12: Apoptosis and neurological disorders

Upstream caspases activate in amplifying cascade executioner caspases downstream.

Executioner caspases mediate cell death by two main mechanisms: destruction and activation.

Page 13: Apoptosis and neurological disorders

Cytochrome c-member of the mitochondrial electron-transport chain required for generation of ATP.

Important trigger of caspase cascade.

Activation occurs by release of cytochrome c is released from mitochondria into the cytoplasm.

Binds to Apaf-1 to form the apoptosome — a molecular complex consisting of cytochrome c, Apaf-1, ATP, and procaspase 9.

->Activates caspase 9, 30,52 -upstream initiator of apoptosis.

Page 14: Apoptosis and neurological disorders

Members of Bcl-2 family are proapoptotic or antiapoptotic.

Balance between two has a crucial role in release of cytochrome c

Members of caspase family can influence balance of proapoptotic and antiapoptoticsignals.

For eg. caspase 8 and caspase 1 cleave Bid, a member of Bcl-2 family, generating a truncated fragment with proapoptotic activity.

Page 15: Apoptosis and neurological disorders

Inhibitors interact directly with modulators of cell death.

For Eg. X-linked inhibitor of apoptosis and neuronal inhibitor of apoptosis are proteins in neurons that directly inhibit caspase 3 activity and protect neurons from ischemic injury.

Page 16: Apoptosis and neurological disorders

P53 first arrests cell growth between G1 S

This allows for DNA repair during delay

If the damage is too extensive then p53 induces gene activation leading to apoptosis (programmed cell death)

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Important in normal physiology / development– Development: Immune systems maturation,

Morphogenesis, Neural development

– Adult: Immune privilege, DNA Damage and wound repair.

Excess apoptosis– Neurodegenerative diseases

Deficient apoptosis– Cancer

– Autoimmunity

Page 22: Apoptosis and neurological disorders

Difference between acute and chronic neurologic diseases is magnitude of stimulus causing cell death.

Greater stimulus in acute diseases results in both necrotic and apoptotic cell death

Milder insults in chronic diseases initiate apoptotic cell death.

Page 23: Apoptosis and neurological disorders

Activation of caspases1, 3, 8, 9, and 11 and release of cytochrome c seen in cerebral ischemia,

Mice that express a dominant-negative caspase 1 construct or that are deficient in caspase 1 or caspase11 have significant protection from ischemic injury.

Mice T/T with broad caspase inhibitor/semiselectiveinhibitors of caspase 1 & 3 protect from ischemia.

Pattern of combined necrotic and apoptotic cell death after ischemic or traumatic injury.

Necrotic cell death-core of infarction.

Ischemic penumbra-activate caspase cascade.

Page 24: Apoptosis and neurological disorders

TBI-apoptosis-related changes in neurons like presence of DNA strand breaks, caspaseactivation, increased Bax, p53 expression.

Intraventricular administration of caspase-3 inhibitor z-DEVD-fmk before injury reduces cell death and improves symptoms.

Mice expressing dominant-negative inhibitor of caspase-1 show reduced brain damage and free radical production after TBI.

Page 25: Apoptosis and neurological disorders

Intraventricular infusion of NGF in rats resulted in improved learning and memory and decreased death of neurons in TBI.

Cyclosporin A protects against synaptic dysfunction and cell death in rodent models of TBI.

In rodents, SCI can be prevented by glutamate-receptor antagonists.

Page 26: Apoptosis and neurological disorders

Degenerating neurons show aggregates of hyperphosphorylated tau protein & excessive calcium-mediated proteolysis and oxidative stress.

Increased DNA damage & caspase activity

Alterations in expression of apoptosis-related genes such as Bcl-2 family members, Par- 4 and DNA damage response genes.

Marked decrease in expression of anti-apoptotic gene called NCKAP1

Page 27: Apoptosis and neurological disorders

Amyloid-β sensitizes neurons to death involves membrane lipid peroxidation

Impairs function of membrane ionmotiveATPases and glucose and glutamate transporters resulting in membrane depolarization, ATP depletion, excessive calcium influx and mitochondrial dysfunction.

APP-substrate for caspase-3 Caspase-mediated cleavage of APP release a

carboxy-terminal peptide called C31, a potent inducer of apoptosis

Page 28: Apoptosis and neurological disorders

Presenilin-1 mutation leads to disturbances in calcium homeostasis in endoplasmic reticulum (ER) such that more calcium is released in neurons.

Neurotrophic factors,cytokines known to prevent neuronal apoptosis

Page 29: Apoptosis and neurological disorders

Increased oxidative stress and mitochondrial dysfunction in dopamine neurons are central to disease.

Deficit in Mitochondrial Complex I which may arise from or contribute to increased cellular oxidative stress.

Environmental and genetic factors sensitizes neurons to oxidative stress.

Monkeys and people exposed to toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) show Parkinson’s-like symptoms

Page 30: Apoptosis and neurological disorders

Apoptosis-related DNA damage and gene activation seen in death of dopamine neurons

Levels of Par-4 are selectively increased

Suppression of Par-4 expression protects dopamine neurons against death

Caspase-1 inhibition, glial cell-derived neurotrophic factor (GDNF) can protect dopamine neurons.

Expression of mutant α-synuclein in cultured cells promotes apoptosis.

Page 31: Apoptosis and neurological disorders

Impaired mitochondrial function and excitotoxicdeath may be central to disease.

Studies of Lymphoblasts from patients with Huntington’s disease showed increased stress induced apoptosis associated with mitochondrial dysfunction

Increased caspase-3 activation.

Mutant huntingtin in cultured cells induces caspase8-dependent apoptosis.

Huntingtin can be cleaved by caspases, which may promote protein aggregation and neurotoxicity.

Inhibition of caspase-1 was reported to slow disease progression in mouse models.

Page 32: Apoptosis and neurological disorders

Increased oxidative stress, overactivation of glutamate receptors and cellular calcium overload.

Autoantibodies against voltage-dependent calcium channels.

Mutations in antioxidant enzyme Cu/Zn-superoxide dismutase (SOD)

Increased peroxidase activity.

In ALS DNA starts to fragment between nucleosomes(a sign of nuclear apoptosis) in neurons within the spinal-cord anterior horn and motor cortex.

Levels of Bax, but not Bcl-2, are increased in spinal-cord motor neurons of ALS patients.

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Vitamin E, melatonin, resveratrol, carnosine, coenzyme Q10

Vit E-slightly delays disease progression in patients with moderately severe AD and PD and can improve the cognitive function in AD patients

Some clinical trials showed vitamin E actually aggravated AD

Page 35: Apoptosis and neurological disorders

Polyphenol with powerful antioxidant properties

Abundant component of red wine

May cause increased neuroprotective activity through activation of sirtuin 1 (SIRT1)

SIRT1 exerts antiapoptotic and neuroprotectiveeffects by deacetylating transcription factors, such as the tumour suppressor p53, the FOXO family of proteins (also called FKHR, a member of the Forkhead family of transcription factors), and NF-B.

SIRT1 activation also has anti-aging properties in invertebrates.

Page 36: Apoptosis and neurological disorders

Radical scavenger, anti-apoptotic and anti-aging properties.

Prevents mitochondrial calcium overload, mitochondrial depolarization, ROS formation, opening of mitochondrial permeability transition pore (PTP) that precedes Cyt c release.

Clinical trial in PD patients, melatonin (3mg) did not improve motor dysfunction abnormalities but some beneficial effects noted in quality of sleep.

In AD patients-beneficial effects of melatonin (3 to 9 mg) on memory loss are unclear.

Page 37: Apoptosis and neurological disorders

Clinical trials showed that combining carnosine (daily dose of 1.5 g for 30 days) with the conventional treatment for PD significantly improves neurological status and locomotor performance.

Could be used as an anti-aging treatment as well as in AD treatment.

No clinical trials of using this drug in AD

No publication of data on the effects of carnosine on cognitive function.

Page 38: Apoptosis and neurological disorders

Cofactor of electron transport chain.

Prevents mitochondrial dysfunction

Antioxidant properties.

Evidence that it decreases with aging in both human and rat tissues.

Cognitive performance of patients with AD improved when treated with an antioxidant together with acetylcholinesterase inhibitors.

Phase II clinical trials reports potentially beneficial effects in CoQ10 in PD.

Ongoing research in HD, ALS, PSP.

Page 39: Apoptosis and neurological disorders

Attenuate neurotoxicity in neuronal cell preparations.

Temporarily rescue neurons since these surviving neurons are in a dysfunctional state due to release of pro-apoptotic proteins.

Page 40: Apoptosis and neurological disorders

Two types of calpains u and m-calpain

Proteases when activated induce degradation of cellular substrates such as cytoskeletal proteins, membrane proteins, phosphatases.

Increased calpain immunoreactivity seen in senile plaques of AD and PD brains.

P35->p25->activation of CDK5-> phosphorylation of myocyte enhancing factor2(MEF-2)->apotosis.

CDK5 inhibitor roscovitine- antiapoptotic and neuroprotective effects in several models of neurodegeneration

Page 41: Apoptosis and neurological disorders

Rodent and cell culture models calpaininhibitors such as calpeptin, MDL-28170 and PD150606 shown to prevent neuronal death and restore cognitive function in AD models.

Page 42: Apoptosis and neurological disorders

Ability to phosphorylate a variety of substrates.

Lithium -direct & reversible GSK-3 inhibitor

Also inhibits calpain/CDK5 pathway & modulates NMDA receptor.

Also favours autophagy.

Contradictory results in clinical trials in AD and ALS.

Page 43: Apoptosis and neurological disorders

Newer compounds-Paullones, indirubines, thiazoles, aminopyrimidines and bisindol-maleimides.

ATP inhibitors.

Developed by Glaxosmithkline and AstraZeneca.

Page 44: Apoptosis and neurological disorders

G1/S blockers-flavopiridol, kempaullone and roscovitine showed neuroprotectiveproperties in neuronal cell cultures.

Anticancer drugs.

More side effects.

Page 45: Apoptosis and neurological disorders

Anti-inflammatory properties, decreases microglia activation, free radical formation, prevent excessive intracellular calcium entry via NMDA receptors.

Varied penetration via blood brain barrier (atorvastatin, lovastatin)

Tried in PD, DLB, ALS, MS with varied results.

Page 46: Apoptosis and neurological disorders

Mitigate mitochondrial calcium overload, prevent ROS production, inhibit cyt c release, increase in neurotrophin production

Daily ibuprofen (50 mg/kg) in APP23 AD mice models and in humans caused increase in cognitive activity

R-flurbiprofen –decreased learning impairments in AD

Discouraging results in clinical trials.

Page 47: Apoptosis and neurological disorders

Rosiglitazone, troglitazone-neuroprotectiveeffect against -amyloid-induced cell death.

Capacity to stop inflammatory gene expression in peripheral immune cells

Reduced microglial and astrocyte activation.

Tried in AD, MS

Page 48: Apoptosis and neurological disorders

Prevents release of proapoptoticmitochondrial proteins such as cytochrome c into the cytosol

Upregulates Bcl-2 expression

Reduces cleavage of Bid, a protein of the Bcl-2 family with pro-apoptotic properties

Anti-inflammatory properties through modulation of immune cytokines

Tried in AD,PD,HD,ALS

Page 49: Apoptosis and neurological disorders

Calcium overload which leads to apoptotic cell death

Memantine-uncompetitive NMDA receptor antagonist that blocks with low affinity

Does not interfere with physiological activity of glutamate in learning and memory processes

Dizocilpine, selfotel, aptiganel, remacemide,licostinel-unacceptable side effects.

Page 50: Apoptosis and neurological disorders

NGF role in maintenance of cholinergic neurotransmitter systems in cholinergic forebrain neurons

CERE-110 is a genetically engineered replication defective adeno-associated virus serotype 2 (AAV2) vector

Contains full-length human -nerve growth factor cDNA.

Phase II study in AD BDNF may enhance differentiation and survival of

dopaminergic neurons in substantia nigra. Several small molecules targeted to BDNF

receptors are being developed.

Page 51: Apoptosis and neurological disorders

thanks

Page 52: Apoptosis and neurological disorders

Apoptosis and Caspases in Neurodegenerative Diseases: Robert M. Friedlander: N Engl J Med 348;14:april 3, 2003

Antiapoptotic drugs:A Therapeutic Strategy for the Prevention of Neurodegenerative Diseases;CurrentPharmaceutical Design, 2011, Vol. 17, No. 3 233

Apoptosis In Neurodegenerative Disorders: Mark P.Mattson; Nature Reviews | Molecular Cell Biology Volume 1 | November 2000 | 121

Page 53: Apoptosis and neurological disorders

Neuroprotection in Progressive Brain Disorders; Ruth Djaldetti, Nirit Lev, Eldad Melamed; IMAJ . Vol 5 . August 2003

Gene Transfer of Baculoviral p35 by Adenoviral Vector Protects Human Cerebral Neurons from Apoptosis;DNA AND CELL BIOLOGY;Volume 23, Number 8, 2004

Apoptotic and antiapoptotic mechanisms in stroke; Cell Tissue Res (2000) 301:173–187


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