60 Questions
What is a common feature of neurodegenerative disease?
Chronic inflammation
What is the primary function of the Golgi apparatus in protein folding?
To receive correctly folded proteins from the ER
What is the result of Ca2+ overload and membrane damage in necrosis?
Cell swelling and vacuolization
What is the primary mechanism of neuronal death in chronic neurodegenerative disease?
Apoptosis
What is the outcome of protein misfolding and ubiquitination?
Protein aggregation and neuronal damage
What is the primary cause of ischaemic brain damage?
Acute injury
What is the result of the systematic dismantling of a cell in apoptosis?
Macrophages removing shrunken remnants
What is the result of raised Ca2+ levels in neurons?
Activation of protease and lipase
What is the function of superoxide dismutase (SOD)?
To reduce oxidative stress
What is the effect of neuronal growth factor (NGF) on apoptosis?
It decreases apoptosis
What is the role of mitochondria in excitotoxicity?
To impair energy metabolism
What is the result of nNOS activation?
Increased NO production with cell damage
What is the primary consequence of excessive ROS production in neurodegenerative diseases?
Oxidative stress
What is the primary mechanism of ischaemic brain damage?
Exocitotoxicity due to interruption of blood supply
What is the role of SOD, catalase, antioxidants, glutathione, and vitamin E in the body?
To defend against oxidative stress
What is the primary characteristic of the penumbra region in ischaemic brain damage?
Reversible damage
What is the consequence of mitochondrial respiratory chain enzyme mutations?
Increased susceptibility to oxidative stress
What is the percentage of stroke that is ischaemic?
85%
What is the primary component of amorphous extracellular deposits in Alzheimer's disease?
Amyloid protein (Aβ)
Which of the following is a characteristic of Down's syndrome?
Early onset of AD-like dementia
What is the mechanism of action of Memantine in Alzheimer's disease?
Weak antagonism of NMDA receptors
What is the effect of Tacrine on hepatic function?
Hepatotoxicity
What is the estimated prevalence of Parkinson's disease in the UK?
1:500
What is the primary effect of Cholinesterase inhibitors in Alzheimer's disease?
Modest improvement in memory and cognitive tests
What is the primary mechanism of action of alteplase in treating ischaemic brain damage?
Dissolving blood clots
Why is CT scanning required before administering alteplase in ischaemic brain damage?
To rule out haemorrhagic stroke
What is the primary characteristic of Alzheimer's disease?
Loss of cognitive ability with no identifiable cause
What is the region of the brain most affected in Alzheimer's disease?
Hippocampus and basal forebrain
What is the prevalence of Alzheimer's disease at the age of 95 years?
90% or higher
What is the proposed therapeutic approach to treat Alzheimer's disease in the future?
Administering neuroprotective agents to rescue cells
$Ca^{2+}$ overload is a necessary factor for excitotoxicity
True
Neuronal growth factor (NGF) and BDNF increase apoptosis
False
Superoxide dismutase (SOD) is involved in the systematic dismantling of a cell in apoptosis
False
Mitochondrial oxidative phosphorylation generates $NO$
False
Excitotoxicity is characterized by the release of arachidonic acid and the decrease of glutamate reuptake
True
NNOS activation is neuroprotective
False
The primary mechanism of neuronal death in ischaemic brain damage is apoptosis
False
The release of cytochrome c from damaged mitochondria always leads to apoptosis
False
Reperfusion injury in ischaemic brain damage is caused by the release of antioxidants
False
Mitochondrial dysfunction is a minor contributor to neurodegenerative diseases
False
The penumbra region in ischaemic brain damage is characterized by irreversible necrosis
False
Stroke is the leading cause of death globally
False
Alteplase reduces mortality in ischaemic brain damage.
False
CT scanning is required before administering alteplase to diagnose ischaemic brain damage.
True
The prevalence of Alzheimer's disease is 5% at 65 years and 90%+ at 95 years.
True
Surgery is the primary means of treating ischaemic brain damage.
False
Neuroprotective agents are currently used to rescue cells in the penumbral region of ischaemic brain damage.
False
Atherosclerosis is the primary cause of Alzheimer's disease.
False
Neurodegenerative diseases are characterized by a single pathological process causing neuronal damage or death.
False
Ischaemic brain damage is a chronic condition.
False
Normal protein folding occurs in the Golgi apparatus.
False
Apoptosis is a mechanism of neuronal death involving cell swelling and membrane damage.
False
Oxidative stress is a primary mechanism of neuronal death in acute neurodegenerative disease.
False
Neurogenesis is the process of neuronal death in neurodegenerative diseases.
False
All forms of Alzheimer's disease are caused by mutations of the APP gene.
False
Amyloid plaques are composed of phosphorylated Tau protein.
False
Tacrine is effective in treating Alzheimer's disease in all patients.
False
Down's syndrome often leads to late-onset Alzheimer's disease.
False
Memantine is a strong antagonist of NMDA receptors.
False
Parkinson's disease only affects movement control.
False
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
Test your knowledge of neurodegenerative diseases, including mechanisms of neuronal death, protein misfolding, and aggregation. Learn about Alzheimer's and Parkinson's diseases, as well as ischaemic brain damage. Understand the pathological processes causing neuronal damage and death.
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