Neurodegenerative diseases Flashcards
Neurodegenerative diseases
Caused by pathological processes resulting in neuronal damage/death
This damage is irreversible
Occurs under inflammatory conditions, which inhibit neurogenesis
Protein folding
Proteins are folded in the ER by molecular chaperones
However, the folding process is prone to error; improperly folded proteins are identified, ubiquitinated and degraded
The tendency to mis-fold proteins increases with mutations
The proteins may then overwhelm the disposal system and form aggregates which cause cell death
Necrosis
Mechanism of cell death occurring due to acute injury
The cell swells and lyses due to calcium ion overload
Leads to an inflammatory response; perfect conditions for neurodegeneration
Apoptotis
Mechanism of cell death that is physiological
The cell is systematically dismantled and an inflammatory response is prevented
However, apoptosis leads to a reduction in the production of neuronal growth factor and BDNF
Excitotoxicity
Glutamate is highly toxic to neurons
Calcium overload contributes to glutamate release, activates proteases and produces ROS
Excitotoxic cell death
- Glutamate stimulates NMDA and AMPA receptors, leading to an influx of calcium ions, the ER and mitochondria act as sinks for these ions
- At a certain point the loading of mitochondrial stores leads to mitochondrial dysfunction, leading to the production of ROS and reducing ATP synthesis
- ATP is needed to pump calcium out of the cell, so calcium further accumulates in the cell
Ischaemic brain damage
70% of ischaemic brain damage is non-fatal
Ischaemic stroke = occurs due to blockage of key arteries
Haemorrhagic stroke = occurs due to rupture of the cerebral artery
Interruption of the blood supply leads to excitotoxicty in the brain
-This is because there is a build-up of waste products and a lack of oxygen, which stimulates glutamate release
Reperfusion injury
Reperfusion of the brain leads to further injury
This is because influx of oxygen leads to the production of ROS and a penumbra
This injury develops over several hours
Alteplase
A treatment for stroke
A plasminogen activator which breaks down the thrombus
Cannot be used for haemorrhagic stroke, because it would cause further bleeding
Improves psot-injury functionality
Alzheimer’s disease
A loss of cognitive ability
Associated with brain shrinkage and neuronal loss in the hippocampus and basal forebrain
Specific to cholinergic neuronal loss
Amyloid plaques
A feature of Alzheimer’s disease
Extracellular deposits of B-amyloid protein
Occur due to altered processing of amyloid protein, linked to a mutation
The plaques also cause neurofibrillary tangles and cell death
Neurofibrillary tangles
B-amyloid deposits cause the phosphorylation of a protein called Tau
Tau anchors cytoskeletal filaments within the neuron, so phosphorylation causes tangling of the filaments
This limits anterograde/ retrograde movement in the neuron and eventually leads to cell death
Treating Alzheimer’s disease
Alzheimer’s disease has no cure and there are no drugs that halt its progression
Cholinesterase inhibitors such as tacrine have been shown to improve memory and cognition
Have to be taken X4 daily, so compliance is difficult
Parkinson’s disease
A progressive disorder of movement
Symptoms = muscle rigidity, bradykinesia, tremor
Associated with a decrease in dopamine levels and a loss of dopaminergic neurons
Levodopa
Works to increase levels of dopamine
A precursor of dopamine; given because it can pass through the blood-brain barrier
Co-administered with a dopa decarboxylase inhibitor to prevent breakdown of L-dopa before it reaches the brain
Mechanism of action unknown
