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Questions and Answers
What is a common feature of neurodegenerative disease?
What is a common feature of neurodegenerative disease?
- Cellular regeneration
- Acute inflammation
- Chronic inflammation (correct)
- Progenitor cell activation
What is the primary function of the Golgi apparatus in protein folding?
What is the primary function of the Golgi apparatus in protein folding?
- To receive correctly folded proteins from the ER (correct)
- To ubiquitinate misfolded proteins
- To facilitate protein folding into their 3D shape
- To transport folded proteins to the ER
What is the result of Ca2+ overload and membrane damage in necrosis?
What is the result of Ca2+ overload and membrane damage in necrosis?
- Cell shrinkage and apoptosis
- Cell swelling and vacuolization (correct)
- Progenitor cell activation and neurogenesis
- Cellular regeneration and proliferation
What is the primary mechanism of neuronal death in chronic neurodegenerative disease?
What is the primary mechanism of neuronal death in chronic neurodegenerative disease?
What is the outcome of protein misfolding and ubiquitination?
What is the outcome of protein misfolding and ubiquitination?
What is the primary cause of ischaemic brain damage?
What is the primary cause of ischaemic brain damage?
What is the result of the systematic dismantling of a cell in apoptosis?
What is the result of the systematic dismantling of a cell in apoptosis?
What is the result of raised Ca2+ levels in neurons?
What is the result of raised Ca2+ levels in neurons?
What is the function of superoxide dismutase (SOD)?
What is the function of superoxide dismutase (SOD)?
What is the effect of neuronal growth factor (NGF) on apoptosis?
What is the effect of neuronal growth factor (NGF) on apoptosis?
What is the role of mitochondria in excitotoxicity?
What is the role of mitochondria in excitotoxicity?
What is the result of nNOS activation?
What is the result of nNOS activation?
What is the primary consequence of excessive ROS production in neurodegenerative diseases?
What is the primary consequence of excessive ROS production in neurodegenerative diseases?
What is the primary mechanism of ischaemic brain damage?
What is the primary mechanism of ischaemic brain damage?
What is the role of SOD, catalase, antioxidants, glutathione, and vitamin E in the body?
What is the role of SOD, catalase, antioxidants, glutathione, and vitamin E in the body?
What is the primary characteristic of the penumbra region in ischaemic brain damage?
What is the primary characteristic of the penumbra region in ischaemic brain damage?
What is the consequence of mitochondrial respiratory chain enzyme mutations?
What is the consequence of mitochondrial respiratory chain enzyme mutations?
What is the percentage of stroke that is ischaemic?
What is the percentage of stroke that is ischaemic?
What is the primary component of amorphous extracellular deposits in Alzheimer's disease?
What is the primary component of amorphous extracellular deposits in Alzheimer's disease?
Which of the following is a characteristic of Down's syndrome?
Which of the following is a characteristic of Down's syndrome?
What is the mechanism of action of Memantine in Alzheimer's disease?
What is the mechanism of action of Memantine in Alzheimer's disease?
What is the effect of Tacrine on hepatic function?
What is the effect of Tacrine on hepatic function?
What is the estimated prevalence of Parkinson's disease in the UK?
What is the estimated prevalence of Parkinson's disease in the UK?
What is the primary effect of Cholinesterase inhibitors in Alzheimer's disease?
What is the primary effect of Cholinesterase inhibitors in Alzheimer's disease?
What is the primary mechanism of action of alteplase in treating ischaemic brain damage?
What is the primary mechanism of action of alteplase in treating ischaemic brain damage?
Why is CT scanning required before administering alteplase in ischaemic brain damage?
Why is CT scanning required before administering alteplase in ischaemic brain damage?
What is the primary characteristic of Alzheimer's disease?
What is the primary characteristic of Alzheimer's disease?
What is the region of the brain most affected in Alzheimer's disease?
What is the region of the brain most affected in Alzheimer's disease?
What is the prevalence of Alzheimer's disease at the age of 95 years?
What is the prevalence of Alzheimer's disease at the age of 95 years?
What is the proposed therapeutic approach to treat Alzheimer's disease in the future?
What is the proposed therapeutic approach to treat Alzheimer's disease in the future?
$Ca^{2+}$ overload is a necessary factor for excitotoxicity
$Ca^{2+}$ overload is a necessary factor for excitotoxicity
Neuronal growth factor (NGF) and BDNF increase apoptosis
Neuronal growth factor (NGF) and BDNF increase apoptosis
Superoxide dismutase (SOD) is involved in the systematic dismantling of a cell in apoptosis
Superoxide dismutase (SOD) is involved in the systematic dismantling of a cell in apoptosis
Mitochondrial oxidative phosphorylation generates $NO$
Mitochondrial oxidative phosphorylation generates $NO$
Excitotoxicity is characterized by the release of arachidonic acid and the decrease of glutamate reuptake
Excitotoxicity is characterized by the release of arachidonic acid and the decrease of glutamate reuptake
NNOS activation is neuroprotective
NNOS activation is neuroprotective
The primary mechanism of neuronal death in ischaemic brain damage is apoptosis
The primary mechanism of neuronal death in ischaemic brain damage is apoptosis
The release of cytochrome c from damaged mitochondria always leads to apoptosis
The release of cytochrome c from damaged mitochondria always leads to apoptosis
Reperfusion injury in ischaemic brain damage is caused by the release of antioxidants
Reperfusion injury in ischaemic brain damage is caused by the release of antioxidants
Mitochondrial dysfunction is a minor contributor to neurodegenerative diseases
Mitochondrial dysfunction is a minor contributor to neurodegenerative diseases
The penumbra region in ischaemic brain damage is characterized by irreversible necrosis
The penumbra region in ischaemic brain damage is characterized by irreversible necrosis
Stroke is the leading cause of death globally
Stroke is the leading cause of death globally
Alteplase reduces mortality in ischaemic brain damage.
Alteplase reduces mortality in ischaemic brain damage.
CT scanning is required before administering alteplase to diagnose ischaemic brain damage.
CT scanning is required before administering alteplase to diagnose ischaemic brain damage.
The prevalence of Alzheimer's disease is 5% at 65 years and 90%+ at 95 years.
The prevalence of Alzheimer's disease is 5% at 65 years and 90%+ at 95 years.
Surgery is the primary means of treating ischaemic brain damage.
Surgery is the primary means of treating ischaemic brain damage.
Neuroprotective agents are currently used to rescue cells in the penumbral region of ischaemic brain damage.
Neuroprotective agents are currently used to rescue cells in the penumbral region of ischaemic brain damage.
Atherosclerosis is the primary cause of Alzheimer's disease.
Atherosclerosis is the primary cause of Alzheimer's disease.
Neurodegenerative diseases are characterized by a single pathological process causing neuronal damage or death.
Neurodegenerative diseases are characterized by a single pathological process causing neuronal damage or death.
Ischaemic brain damage is a chronic condition.
Ischaemic brain damage is a chronic condition.
Normal protein folding occurs in the Golgi apparatus.
Normal protein folding occurs in the Golgi apparatus.
Apoptosis is a mechanism of neuronal death involving cell swelling and membrane damage.
Apoptosis is a mechanism of neuronal death involving cell swelling and membrane damage.
Oxidative stress is a primary mechanism of neuronal death in acute neurodegenerative disease.
Oxidative stress is a primary mechanism of neuronal death in acute neurodegenerative disease.
Neurogenesis is the process of neuronal death in neurodegenerative diseases.
Neurogenesis is the process of neuronal death in neurodegenerative diseases.
All forms of Alzheimer's disease are caused by mutations of the APP gene.
All forms of Alzheimer's disease are caused by mutations of the APP gene.
Amyloid plaques are composed of phosphorylated Tau protein.
Amyloid plaques are composed of phosphorylated Tau protein.
Tacrine is effective in treating Alzheimer's disease in all patients.
Tacrine is effective in treating Alzheimer's disease in all patients.
Down's syndrome often leads to late-onset Alzheimer's disease.
Down's syndrome often leads to late-onset Alzheimer's disease.
Memantine is a strong antagonist of NMDA receptors.
Memantine is a strong antagonist of NMDA receptors.
Parkinson's disease only affects movement control.
Parkinson's disease only affects movement control.
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Study Notes
Mechanisms of Neuronal Death
- 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) and BDNF: ↓apoptosis, ↓Bax (pro-apoptotic) and ↑Bcl-2 (anti-apoptotic)
Excitotoxicity
- Glutamate (Glu): highly toxic to neurons, Ca2+ overload is an essential factor
- Raised [Ca2+]: ↑Glu release, ↑protease and lipase activation, activation of nNOS
- ↓[NO]: neuroprotective, ↑[NO] + ROS = cell damage
- ↑arachidonic acid release: ↑ROS and ↓Glu reuptake
Oxidative Stress
- Mitochondrial oxidative phosphorylation: generates ATP
- Mitochondrial energy metabolism: impaired mitochondria, Parkinson's, Stroke
- Superoxide dismutase (SOD): defence against oxidative stress
Neurodegenerative Diseases
- Pathological process(es) causing neuronal damage/death
- Neurogenesis: formation of neurons from progenitor cells
- Ischaemic brain damage (stroke): acute
- Alzheimer's disease: chronic
- Parkinson's disease: chronic
Protein Misfolding and Aggregation
- Proteins folded to their 3D shape in ER
- √ folded proteins → golgi
- X folded proteins → ubiquinated
- Protein misfolding and aggregation: essential mechanism in neurodegenerative diseases
Ischaemic Brain Damage
- Necrosis: due to acute injury, cell swells, Ca2+ overload, membrane damage, cell swelling, vacuolisation, and lysis
- Spills contents of cell into surrounding tissue: inflammatory response
- Chronic inflammation: feature of neurodegenerative disease
- Alteplase: plasminogen activator, disperses thrombus, reduces mortality, but significant functional benefit
Alzheimer's Disease
- Loss of cognitive ability with age: normal
- AD: dementia that does not have a cause
- Prevalence rises with age: 5% at 65yrs to 90%+ at 95yrs
- Age-related dementia: accelerated neuronal loss, falling blood supply due to atherosclerosis
- Associated with brain shrinkage and localised loss of neurons: hippocampus and basal forebrain
- Loss of cholinergic neurons: hippocampus and frontal cortex
Pathogenesis of Alzheimer's Disease
- Excessive ROS production: oxidative stress, NO synthesis, arachidonic acid metabolism
- Reperfusion: leukocytes release cytotoxic oxygen, damages DNA, enzymes, and membrane lipids
Oxidative Stress and Defence Mechanisms
- Defence mechanisms: SOD, catalase, antioxidants, glutathione, and vitamin E
- Oxidative stress: cause and consequence of inflammation
- Mitochondrial integrity: essential for neuronal survival
- Mitochondrial respiratory chain enzyme mutations: congenital or age-related, ↑in susceptibility to oxidative stress
- Damaged mitochondria: cytochrome c release, pro-apoptotic
Ischaemic Brain Damage
- Stroke: 2nd most common cause of death globally (WHO, 2015)
- 70% of stroke: non-fatal
- 85% of stroke: ischaemic
- Thrombosis/blockage of artery
- 15% haemorrhagic: rupture of a cerebral artery
- Interruption to blood supply: exocitotoxicity
- Central core: irreversible necrosis
- Reperfusion: production of ROS on restoration of O2
- Takes hrs to develop: therapeutic opportunity
- Penumbra surrounds core: inflammation and cell death
Therapeutics
- No drugs to halt AD
- Cholinesterase inhibitors: tacrine, modest improvement in memory and cognitive tests
- Memantine: weak antagonist of NMDA, potential inhibitor of excitotoxicity
- Modest cognitive improvement, not neuroprotective
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