Neurodegeneration (8.6)

Question 1

Describe the main mechanisms involved in neuronal cell death

Answer 1

Apoptosis:

• Controlled cell death
• Activation of destructive enzymes and controlled disposal of cellular components
• Physiological role: Synaptic ‘pruning’, allows for the death of damaged cells

Necrosis:

• Uncontrolled cell death which may follow damage/ischaemia
• Loss of ATPase function leads to disrupted cellular permeabilty. Cell swell and then burst. Cell contents leak into the surrounding area, prompting an inflammatory response

Question 2

Describe the distinguishing features of necrosis and apoptosis in the CNS

Answer 2

Question 3

Describe the different causes of cell death

Answer 3

1. Excitotoxicity

Excessive/prolonged stimulation → depolarisation of the membrane (loss of Na⁺ and K⁺ ATPase function) → influx of Ca²⁺ → NT release → reuptake systems overwhelmed → further receptor activation

Outcomes: Activation of harmful enzymes, excessive NO production

2. Oxidative stress

Reactive oxygen species damage cell membranes, leading to cell death.

Scavenger mechanisms are overwhelmed.

3. NO

NO causes protein damage (through interactions with Cys and Tyr), also contributing to cell death.

Question 4

Describe the general features of neurodegenerative diseases

Answer 4

Neuronal loss (following death of neurones) and accumulation of abnormally folded proteins

*Protein accumulation within the neurones may cause neuronal cell death.*

Question 5

Describe the main clinical and neuropathological features of: Alzheimer’s, Parkinson’s and Huntington’s

Answer 5

Question 6

Describe the factors which contribute to neurodegenerative diseases

Answer 6

Characterised by: Selective loss of neuronal populations and abnormal accumulation of protein

• Neuronal cell death
• Genetics: APOE4, E3 ligase, huntingtin gene
• Environmental exposure
• Protein accumulation: Beta-amyloid, tau, alpha-synuclein, polyglutamine inclusions
• Cell membrane damage ⇒ influx of Ca²⁺ ⇒ excitotoxicity
• Production of ROS/NO