09 10 2014 Neurodegenrative disease Flashcards Preview

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Flashcards in 09 10 2014 Neurodegenrative disease Deck (46):
1

Wallerian degeneration

Neuron death
process of axonal degeneration distal to the site of transection.
-dying back phenomena and a retrograde destruction of the nerve cell body.

2

Necrosis

cell swelling with subsequent changes within cell.

-mitochondrial swelling, loss of ATP stores, mitochondrial dysfunction= production of reactive oxygen species.

- cell swelling causes membrane rupture and release of contents.

3

What degenerative states can necrosis be seen in?

- stroke
- hypoxia-ischemia conditions

4

Apoptosis

programmed cell death
-release of mitochondrial cytochrome c and activation of cellular caspases

5

What neurons are selectively vulnerable in the following disease:
-Parkinson's
-Alzeihmer's disease
-Huntington's
-ALS

-nigrostriatal Dopamine neurons (not mesolimbic DA neurons)

-hippocampus/neocortex

-Striatum even though mutated gene is throughout brain

-upper and lower motor neurons

6

Pathway that is common to most forms of neurodegeneration

Dysfunctional mitochondria
= ROS, RNS, Neuroimmune Response
= Proteins/aggregates/proteasomal degradation
=disturbed calcium homeostasis
= Apoptotic pathways.

7

What is the "circle" of events that have caused many to believe that neurons may initiate neurodegeneration?

Intracellular dysfunction in neurons initiate damage and neuron releases contents.

Contents are detected by glial cells and cause an immune response that propagates neurodegeneration.

8

Microglia

(Who are they and how are they in the quiescent/surveillance state?)

Glial cell that are resident macrophages of brain and spinal cord

-distributed in large non-overlapping areas. They are the brain's "radar system.

-Extensive branching

-produce low levels of pro-inflammatory cytokines.

9

Microglia

(Activated state)

Activated by pathogens, viruses, cellular debris, ATP, adenosine, neuropeptides, and cytokines

-lose extensive branching and become Amoeboid --> allows phagocytosis.

-Up-regulate receptors to enhance immune response

- High expression of pro-inflammatory cytokines.

10

How can prolonged Microglial activation can be harmful?

1. Excessive oxidative and nitrosative stress
(ROS/RNS)
2. Pro-inflammatory Molecules

11

What are the general role of Astrocytes?

Neuroprotective role.

-metabolic and homeostatic functions---support for neurons

* maintain BBB*-- support for endothelial cells

-removal of glutamate from extracellular space and reduce excitotoxicity.

12

Astrocytic neuroinflammation responses can be deleterious to neurons:

1. release alpha-synuclein
-degeneration of dopamine neurons = Parkinson's disease

2. pro-inflammatory molecules

3. morphological changes -- sever reactive astrocytes = glial scars
-neuroportective barriers that negatively impact neuronal recovery from insult

4. activate microglial response

5. reactive astrocytes can't upatek glutamate= excitotoxicity = ALS

13

Glial Scars?

How are they good, how are they bad?

1. promote tissue repair and may impair movement of infections agents

BUT

2. prevent axonal or dendritic regeneration and reconnections

14

Who are the molecular players in neurodegeneration?

-ROS
-RNS (reactive nitrogen species)
-Gluatame = excitotoxicity
-Abnormal proteins

15

ROS

Who makes them and how are they taken away from the system?

-mitochondrial dysfunction, activated Microglia

Superoxide dismutase --> H2O2
H2O2--> H2O by Glutathione peroxidase

H2O2 --Fenton rxn-->HO radical

16

Neuroprotective strategies to deal with ROS?

1. increase superoxide dismutase (SOD)
2. Remove peroxynitries
3. Free radical scavengers
4. Reduce iron chelators (tag it to molecule that will pass the BBB)
5. Increase Glutathione levels
6. Block NO synthesis (NO makes peroxynitrites)

17

Nitrosylation

post-translational modification that causes protein aggregation.

Leads to activation of NMDA receptors

--links excitotoxicity with aberrant nitrosylation of proteins.

-increase in RNS!!

18

Excitotoxicity

neuronal damage due to glutamate actions through the N-methy-D-aspartate receptor (NMDA)

Damage due to increase in extracellular glutamate.

-stroke, ischemia, and ALS (also contributes to many others -- PD, AD, MS, seizures, and HD)

19

Excessive NMDA activation causes?

1. dramatic increase in calcium and sodium influx

2. enhances activity of proteases, phospholipase,and NOS

3. comprise membrane potential leading to enhanced NMDA activation

4. Enhances NO production (linking excitotoxicity and nitrosative stress)

20

Mechanisms for reducing excitotoxicity?

1. block NMDA receptor
-NMDA antagonsist
- block essential sites of receptor to dampen activity.

2. Reduce glutamate release
Drug: riluzole (approved for ALS)

3. Enhance glutamate uptake by astrocytes
Drug: ceftriaxone (ineffective for ALS)

21

Mitochondria -- key players in neurodegeneration.

How does dysfunction arise?

1. mutations in genes
-Pink1
-DJ-1 = parkinson disease
-Parkin

2. cellular oxidative damage (mtDNA is susceptible to oxidative stress)
-mitochondrial dysfunction = increase in
ROS

3. altered mitochondrial morpholgy

4. interactions of pathogenic proteins with mitochondria (toxins/pesticides)
- Rotenone

5. mitochondria are more likely to become defective with age.

22

potential target for repair of mitochondria

1. by-pass mitochondria and provide energy substrates to neurons

2. block apoptosis ( cytochrome C release)

3. enhance clearance of defective mitochondria

4. Block NMDA receptors (block excitotoxicity)


Note. if damaged mitochondria stay in the cytosol, then they remain active!! This is bad for cell.

23

Effect of misfolded proteins in neurodegenerative disorders

1. loss of protein function

2. increase in misfolded or damaged proteins place greater demand on proteasomal or autophagy pathways --> pathways can't handle it.

3. Misfolded proteins may "seed" misfiling of normal proteins
- lead to aggregation

24

Prion-like propagation of neurodegeneration

Cell-cell transfer of toxic substances in PD (alpha-synuclein) and AD (alpha-beta 42)

Abnormal protein is taken up by unaffected cell and interacts with normal protein = aggregation of native protein
-Alzeihmer's and Parkinson's

25

Strategies for neurprotection: (who are you targeting?)

1. oxidative stress
-boost antioxidants prevent ROS/RNS
production.

2. Mitochondria
- boost energy, block caspases and pro-
apoptotic signals.

3. Immune response
- block immune response, anti-inflammatory
agents, reduce microglial activation.

4. Excitotoxicity
-reduce glutamate actions (increase uptake)
- block NMDA

26

Parkinson's disease

neurodegenerating disorder
-greates neuronal loss is of nigrostriatal dopamine neurons
= impairment of motor function

Also loss of locus coeruleus noradrenergic neurons and dorsal rap he serotonergic neurons in brain.
= non-motor symptoms seen in PD

Sporadic; familial forms are due to mutations in Synuclein , the Ubiquitin-proteosomal pathway, and mitochondria.

27

lewy bodies

cardinal pathological feature of PD

-rich in alpha- synuclein (can modulate dopamine release -- can impure dopamine release)

28

PET scanning of PD

Imaging of Dopamine transporter in Caudate -- Putamen

- decrease and its is unilateral.

29

If you look at a slide of PD brain what will you see?

(Substantia Nigra)

-loss of pigmented neurons and lewly bodies in Substantia Nigra

30

Oxidative stress is involved in PD. What are the sources?

-dopamine oxidation
-defective mitochondria
-microglial activation
-high iron content in substantial nigra (fenton rxn -- H2O2)

31

Neuroprotective mechanisms for increase in oxidative stress in PD

- decrease MAO (monoamine oxidase)
-Increase Glutathione peroxidase
-reduce iron
-increase antioxidants

32

Mechanism of PD pathogenesis?

1. oxidative stress
2. mitochondrial dysfunction
3. protein aggregation
4. Neuroinflammation
5. Excitotoxicity
6. Apoptosis and cell pathway
7. loss of neurotrophic factors

33

How to battle oxidative stress in PD

1. inhibit dopamine mechanism

2. Iron chelators -- high iron content in substantia nigra

3. enhance antioxidants/ Glutathione process

4. Increase uric acid levels

34

How to battle mitochondrial dysfunction in PD

1. enhance electron transport function (failed clinical trials)

2. block caspase activation (failed clinical trials)

3. Provide energy substrates (creatine is in clinical trials)

35

How to battle protein aggregation in PD?

1. Inhibit synuclein formation

2. Enhance autophagy/ ubiquitin pathway -- preclinical studies actually show a worsening of this -->excessive removal of important cellular components.

36

How to battle neuroinflamamtion in PD

-anti-inflammatory agents (no evidence of efficacy)
-block pro-inflammaotry responses
-dampen microglia activation

37

How to battle excitotoxicity

-reduce NMDA receptor function
-Reduce calcium influx
(isradipide-- calcium blocker--clinical trials)

38

How to battle apopotosis in PD

anti-apoptotic agents

39

how to battle loss of neurotrophic factors

stimulate endogenous production of neurtrophic factors
- cogane -- clinical trials

40

Other two neuroprotective approaches for PD

1. gene therapy
2. Life-style : EXERCISE

41

ALS

rapidly progressive fatal motor neuron disease.
upper and motor neuron
-usually one is affected first and then the other one is too.
-Wallerian degeneration

-degeneration of motor neurons in primary motor cortex, brainstem, spinal cord.

42

what are the muscles affected by ALS?

VOLUNTARY MUSCLES!!!
-leg
-arm
-tongue
-respiratory

43

Genetics of ALS

SOD1 (superoxide dismutase) mutation
-increase ROS, RNS, mitochondria
dysfunctions, protease disruption, microglial
activation.

TDP43 (DNA binding protein -- regulator of transcription)

UBQLN2 (ubiquitin-like protein) -- mutations lead to abnormal protein aggregation
-inclusion bodies

44

What are the primary causes of astrocyte dysfunction in ALS?

1. loss of neuroprotection: defective glutamate uptake leading to excitotoxicity

2. Gain of toxic function : SOD 1 mutation

45

Potential neuroprotective strategy for reducing excitotoxicity in astrocytes

increased glutamate levels in CSF

1. Riluzole : reduces glutamate release

2. Ceftriaxone -- enhance glutamate uptake by astrocyte.

46

Potential sites for ALS neuroprotection (in general)

1. block glutamate release
2. block glutamate uptake by astrocytes
3. block mutant protein expression
4. remove misfolded protein.
5. Enhance normal folding of proteins
6. Enhance mitochondrial funciton
7. Block apoptosis
8. provide growth factors
9. Stem cell transplants