What is apoptosis?

What organelle decides when apoptosis occurs?

When do neurons undergo apoptosis? 2

What are the steps of apoptosis? 3

- Programmed cell death

- The mitochondria

- If it doesn't synapse

- If it does not produce action potential

1) Neuclear envelop breakdown

2) Bebbing/cells fragmentation

3) Phagocytized

What is necrosis?

What is the major difference between necrosis & apoptosis?

What happens to neurons that undergo necrosis?

- Cell death due to injury

- Necrosis -> cell bursting & inflamation

- They are not replaced or slowly replaced

What are the symptoms of alzheimer's? 2

What effect does alzheimer's have on the brain?

What specific areas are effected?

- Memory impairment

- Cognitive decline

- Neural loss shrinks brain

- Hippocampus (memory)

- Association cortex

What 2 aggregates are found in a brain affected with alzheimer's?

What is the main compontent of 1?

What is the main compontent of 2?

What is 2 associated with?

What area does 1 affect?

 What areas does 2 affect? 2

1) Senile plaques

2) Neurofibrillary tangles

1) Amyloid beta 42 (AB42)

2) Hyperphosphorylated tau protein

- Microtubules

- Association cortices

- Hippocampus

- Medial temporal cortex

What alzhimer's pathology does this show?

[image]

What alzhimer's pathology does this show?

What procces does this interupt?

[image]

- Neurofibrillary tangles

- Vesicle transport

What increases cell death in AD?

Why do the protein agregates disturpt cell function?

- Immune system trageting protein aggregates (Neurofibrillary tangles & senile plaques)

- They are insoluable -> causes them to tangle

What is thought to cause AD?

What are the 2 types of AD?

- Genetics

- Early & late onset

What is early-onset (familial) AD caused by? 2

For cause 1, what process is interupted?

What function does AB42 have?

What function does cause 2 have?

What happens when there is a malfunction of 2?

Mutations in genes encoding

1) Amyloid precursor protein (APP)

2) Presenilin 1 & 2

- Cleavage of beta-amyloid (AB) -> AB42 (AB42 becomes senile plaque)

- Regulates synaptic transmission

- Axon support

- Cleaves APP

- Formation of senile plaque

What causes late-onset AD?

What is its function normally?

What is the main cause of AD?

- Malfunction of E 4 allele (APOE4)

- Cholesterol uptake & distribution

- Genetics

What type of receptors are lost in AD?

What pathology does this lead to?

- Selective loss of neurons releasing ACh

- Memory loss & cognative impairments

- Cholinesterase inhibitors

- Glutamate (NMDA) receptor noncompetative antagonists

- nACh receptor agonists

- Don-e-pe-zil

- Tac-rine

- Ri-va-stig-mine

- Ga-lan-ta-mine

Cholinesterase inhibitors

What is the main effect of choinesterase inhibitors?

What effect is seen physically?

How do they work?

Used to treat?

- Increase cholinergic neurotransmission in remaining synapses

- Cognitive improvements

- Prevent breakdown of NT in synaptic cleft

(compensates for decrease in # of synapses)

- AD

What are the 2 NMDA receptor noncompetative antagonist drugs?

Used to treat?

- Memantadine

- Glutamate

- AD

Memantadine

What happens to glutamatergic NT in a patient w AD?

How do glutamate receptor noncompetitive antagonists effect AD patients?

- Glutamateric transmission becomes hyper -> toxic amounts of Ca -> neuronal death

- Reduces toxicity & rate of glutamate receptor

nAChR agonists:

How does it work?

- Prevent senile plaques

- Prevent neurofibrillary tangle formation

How are senile plaques prevented? 3

- Block AB agregation

- AB42 vaccine

- Inhibit cleavage of APP -> AB42

- Sy-clo-hexane-hexols

- Tra-mi-pro-sate

How are neurofibrillary tangle formations prevented?

Why is this a difficult approach?

- Regulating kinase activity

- Kinases have many substrates

- Tremor

- Regidity

- Bradykinesia

- Cognative disturbances

What does PD target & distroy?

Specifically, in what part of the brain?

What forms in the brain to cause damage?

- Dopaminergic projection neurons (nigrostriatal dopaminergic pathway)

- Nigra par compacta

- Lewy bodies

What are Lewy bodies?

What causes them?

- Inclusion protein aggregates

- Mutation in a-synclein

What are the 2 divisions of PD?

- Late onset(>50yrs)

- Early onset(<50yrs)

What is the main cause of early onset PD?

What protiens are mutated in PD? 6

- Genetics

- Parkin

- PINK1

- DJ-1

- a-synuclein

- LRRK2

- UCHL-1

Describe the direct pathway NORMAL in individuals & how the receptors are effected the:

- Cerebral cortex glutamate receptors

- Motor output

- Striatum GABA receptors

- Thalmus glutamate receptors

- Compact part of the substantia nigra DA receptors

- Internal globulus pallidus/reticular part of the substantia nigra GABA receptor

DRAW IT OUT:

- ↓

- ↓

- ↓

- ↓

- ↑

- ↑

[image]

Describe the direct pathway in PD individuals & how the receptors are effected the:

1) Cerebral cortex glutamate receptors

2) Motor output

3) Striatum GABA receptors

4) Thalmus glutamate receptors

5) Compact part of the substantia nigra DA receptors

6) Internal globulus pallidus/reticular part of the substantia nigra GABA receptor

DRAW IT OUT:

1) ↑

2) ↑

3) ↑

4) ↑

5) ↓

6) ↓

[image]

Describe the indirect pathway in NORMAL individuals & how the receptors are effected the:

1) Cerebral cortex glutamate receptors

2) Motor output

3) External globulus pallidus GABA receptors

4) Compact part of the substantia nigra DA receptors

5) Striatum GABA receptors

6) Subthalmic nucleus glutamate receptors

7) Thalmus glutamate receptors

8) Internal globulus pallidus/reticular part of the substantia nigra GABA receptor

DRAW IT OUT

1) ↑

2) ↑

3) ↑

4) ↑

5) ↓

6) ↓

7) ↑

8) ↓

 [image]

Describe the indirect pathway in PD individuals & how the receptors are effected the:

1) Cerebral cortex glutamate receptors

2) Motor output

3) External globulus pallidus GABA receptors

4) Compact part of the substantia nigra DA receptors

5) Striatum GABA receptors

6) Subthalmic nucleus glutamate receptors

7) Thalmus glutamate receptors

8) Internal globulus pallidus/reticular part of the substantia nigra GABA receptor

DRAW IT OUT

1) ↓

2) ↓

3) ↓

4) ↓ (NONE)

5) ↑

6) ↑

7) ↓

8) ↑

[image]

- Mitochondrial dysfunction

- a-synuclein aggregation

- Polygentic inheritance -> increase susceptibility to environmental factors

1) Mitochondrial toxins (rotenone=pesticide)

2) Other herbicides

3) Bacterial infection

4) Meavy metals (Al, Mn)

1) Dopamine receptor agonists

2) L-dopa

3) Brain lesion

4) Deep brain stimulation

1) Bro-mo-crip-tine

2) Per-gol-ide

1) Levadopa (L-dopa)

2) Carbidopa

3) Sinemet (L-dopa+carbidopa)

- Subthalamic nucleus

- Internal globus pallidus

What part of the brain is reversibly inactivated w the deep brain stimulation (treat PD)?

- Implant stem cells in compact substantia nigra

- Antioxidants (coenzyme Q10 & Creatine)

- Growth factors (growth & brain derived neutrophic)

- Gene therapy

- Age as a predictor

- Protein agregates

- Inflammation

- Mitochondria pathology