Tut 1: Protein structure and function (Alzheimers) Flashcards
Explain the relationship between affected brain regions and AD.
Neuritic plaques are located in the central core of the amyloid-Beta peptide, is surrounded by degenerating process of neurons.
Neurofibrillary tangles are made up of pair helical filaments consisting of abnormally phosphorylated microtubules associated with TAU proteins. In patients suffering from AD, the affected brain regions were found to show a high density of these plaques and tangles.
Explain the effect of Neuron and synapse loss and how it is though to relate to AD.
AD involves a loss of neurons such as Cholinergic neurons. Nerve cells communicate with one another via specialised junctional structures called synapses. In AD, the loss of these synapses has been found to have the greatest correlation with the cognitive impairment associated with AD. Any effective therapy for AD will require early diagnosis and treatment to prevent neurochemical and structural changes to the brain. (These changes occur decades before symptoms show)
Where are Amyloid-Beta peptides derived from and what happens in the pathway to form these peptides?
ABeta-Peptides are derived from APP which is the abundant neuronal membrane spanning glycoprotein that can be pressed via a non-amyloidogenic neuroprotective pathway or an amyloidogenic neurotoxic pathway.
Within the amyloidogenic pathway, APP is preferentially cleaved by Beta- and Gamma- Secretases leading to the production of ABeta-peptides that are prone to aggregation, hence giving rise to oligomer and fibrils. Oligomers are currently believe to be the neurotoxic species. Mutation to the APP gene in AD leads to an increase in the production of these toxic peptides.
What is the amyloid cascade hypothesis?
It suggests that deposition of amyloid-Beta peptides is the primary event is AD that triggers neuronal disfunction and death. Recent studies within mouse models also suggests that the TAU protein is also required for ABeta neurotoxicity.
Explain the presence of the TAU protein in AD and its normal function within the brain.
TAU is a major microtubule associated protein located in the brain. The phosphorylation stat of TAU at ser, thr and tyr residues if coordinated by a balance between the activity of TAU protein kinases and TAU protein phosphatases. Lesions containing aggregated phosphorylated TAU proteins are found in AD and other disorders, these are collectively known as TAUpathies, and are associated with neurodegeneration.
When the phosphorylation state of TAU is appropriately coordinates;
- TAU binds to microtubules to regulate stability and dynamics as well as regulating neurite outgrowth and axonal transport.
Explain what happens for the TAU protein to be modified in AD patients.
In AD, TAU becomes hyper-phosphorylated due to an imbalance in the phosphorylation/dephosphorylation of TAE, resulting in an increase in kinase activity but a decrease in phosphatase activity.
These highly phosphorylated TAU proteins detach from microtubules and start aggregating. This can result in soluble TAY oligomers which are toxic leading to the loss of normal function and a gain in toxic function.
Explain TAU mediated neurodegeneration
Phosphorylation and dephosphorylation of TAU controls the attachment and detachment of TAY from microtubules. Hyper-phosphorylated TAU induces microtubule disassembly caused an insufficiency in axonal transport. The unbound TAU self-aggregated into oligomers in axons or dendrites, congesting axonal transport.
What is the time course of neurodegeneration and therapies?
The accumulation of abnormal proteins instigate a variety of molecular changes that precede neurophysiological dysfunctions, which lead to clinical symptoms. Appropriate markers and measures are required to detect pre-symptomatic neurological and biological changes in patients with neurodegenerative diseases. Current drugs such as Anti-psychotics, acetylcholinesterase inhibitors, are used to treat symptoms, but have limited therapeutic value. TAU and Amyloid-Beta targetted disease modifying therapeutic approaches are being developed.
List some of the therapeutic strategies that could be used based on the amyloid cascade hypothesis.
- Lowing the amyloid-Beta generation by targetting the enzymes that cleave APP.
- Enhance the facilitation of amyloid-beta clearance via the activated of degrading enzymes or active/passive immunisation
- Preventing the aggregation of amyloid-beta and destabilising the A-Beta oligomers.
- Blocking the interaction of A-Beta with cell surface receptors.
- Modulation downstream pathways to make the brain more resistant against A-Beta, that can be removed effectively and safely.
