Pharmacology. 05/03/20
Neurodegenerative diseases
1. Outline
Neurodegenerative disease mechanisms
- Protein misfolding& aggregation
- Mechanisms of neuronal death
Ischaemic brain damage (stroke)
Alzheimer’s disease
Parkinson’s disease
2. Neurodegenerative diseases
Pathological process(es) causing neuronal damage/death
Neurogenesis –formation of neurons from progenitor cells
Pathological focus of lecture
- Ischaemic brain damage (stroke) –acute, brain not getting oxygen, nutrients and waste
products are not being taken away
- Alzheimer’s disease (chronic), chronic conditions are caused by aggregation of misfolded
variants of proteins which causes an inflammatory response.
- Parkinson’s disease (chronic)
3. Principles to consider....
Protein misfolding& aggregation
- Chronic neurodegenerative disease: Alzheimer’s & Parkinson’s disease
Mechanisms of neuronal death
- Excitotoxicity
- Apoptosis
- Oxidative stress
4. Protein folding
Proteins folded to their 3D shape in ER by molecular
chaperones
√ folded proteins → golgi
X folded proteins → ubiquinated (unfolded) and
proteases degrade protein. This system can be
saturated, proteins need to go somewhere.
5. Protein Misfolding & aggregation
Aggregates sometimes called amyloid
deposits, body recognises as foreign
which creates an inflammatory
response, consistent inflammation leads
to neurotoxicity.
, Pharmacology. 05/03/20
Neurodegenerative diseases
6. Mechanisms of neuronal death
Necrosis
- Due to acute injury, driven by an
inflammatory response.
- Cell swells → Ca2+overload &
membrane damage → cell
swelling → vacuolisation & lysis
- Spills contents of cell into
surrounding tissue →
inflammatory response
- Chronic inflammation -feature of
neurodegenerative disease
Apoptosis: Programmed cell death
- Essential mechanism
- Systematic dismantling of cell –activation of caspases
- Shrunken remnants removed by macrophages
- No inflammatory response
- Neuronal growth factor (NGF) & BDNF ↓apoptosis
o ↓Bax (pro-apoptotic) & ↑Bcl-2 (anti-apoptotic)
Driven by mitochondria, release of
cytochrome C which activates caspases.
Over time this is not as effective, calcium
influx causes release of cytochrome C
therefore activates death cascade (can
lead to more cell death and we end up
with regions with loss of cells)
Neurodegenerative diseases
1. Outline
Neurodegenerative disease mechanisms
- Protein misfolding& aggregation
- Mechanisms of neuronal death
Ischaemic brain damage (stroke)
Alzheimer’s disease
Parkinson’s disease
2. Neurodegenerative diseases
Pathological process(es) causing neuronal damage/death
Neurogenesis –formation of neurons from progenitor cells
Pathological focus of lecture
- Ischaemic brain damage (stroke) –acute, brain not getting oxygen, nutrients and waste
products are not being taken away
- Alzheimer’s disease (chronic), chronic conditions are caused by aggregation of misfolded
variants of proteins which causes an inflammatory response.
- Parkinson’s disease (chronic)
3. Principles to consider....
Protein misfolding& aggregation
- Chronic neurodegenerative disease: Alzheimer’s & Parkinson’s disease
Mechanisms of neuronal death
- Excitotoxicity
- Apoptosis
- Oxidative stress
4. Protein folding
Proteins folded to their 3D shape in ER by molecular
chaperones
√ folded proteins → golgi
X folded proteins → ubiquinated (unfolded) and
proteases degrade protein. This system can be
saturated, proteins need to go somewhere.
5. Protein Misfolding & aggregation
Aggregates sometimes called amyloid
deposits, body recognises as foreign
which creates an inflammatory
response, consistent inflammation leads
to neurotoxicity.
, Pharmacology. 05/03/20
Neurodegenerative diseases
6. Mechanisms of neuronal death
Necrosis
- Due to acute injury, driven by an
inflammatory response.
- Cell swells → Ca2+overload &
membrane damage → cell
swelling → vacuolisation & lysis
- Spills contents of cell into
surrounding tissue →
inflammatory response
- Chronic inflammation -feature of
neurodegenerative disease
Apoptosis: Programmed cell death
- Essential mechanism
- Systematic dismantling of cell –activation of caspases
- Shrunken remnants removed by macrophages
- No inflammatory response
- Neuronal growth factor (NGF) & BDNF ↓apoptosis
o ↓Bax (pro-apoptotic) & ↑Bcl-2 (anti-apoptotic)
Driven by mitochondria, release of
cytochrome C which activates caspases.
Over time this is not as effective, calcium
influx causes release of cytochrome C
therefore activates death cascade (can
lead to more cell death and we end up
with regions with loss of cells)
