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64 Cards in this Set
- Front
- Back
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What are integrins? |
Transmembrane receptors that bridge cell-cell and cell-ECM interactions. When triggered, integrins in turn trigger chemical pathways to the interior (signal transduction), resulting in a response |
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What are laminins? |
Proteins of the ECM, a major component of the basal lamina. Can influence cell differentiation, migration and adhesion. Vital for the maintenance and survival of tissues, providing a structural scaffolding |
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What are neurotrophins/neurotrophic factors? |
Peptides/small proteins that induce the survival, development, and function of neurons. Belong to a class of growth factors. Growth factors such as neurotrophins that promote the survival of neurons are known as neurotrophic factors. |
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What is the neurotrophic factor hypothesis? |
once a developing neuron has grown its process to a target, it competes with other developing neurons of the same type for a limited supply of neurotrophic factor provided by the target |
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Describe the competitive nature of neurons? |
They are created in excess. NGF made by target field - conc gradient created. Neurons that reach target field quickest live and the target field is innervated. |
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What is the purpose of creating excess neurons and not enough NGF to sustain them? |
Kills off neurons that have grown the wrong way. Also for size matching - big finger = more neurotrophins, less die. |
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In terms of regrowth, what is the difference between PNS neurons and CNS neurons? |
Peripheral nerves can regrow, CNS nerves can't due to increased complexity (CNS has multiple neurons talking to the central neuron and therefore has more than one target field) |
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Describe neurotrophic support for the CNS and PNS. |
PNS receive support from target cells, glial cells and connecting neurons. CNS receive support from many more connecting neurons, many more target cells as well as astrocytes. |
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What mammalian neurotrophic factors are there that are A: neurotrophins and B: not related to NGF |
A: NGF, BDNF (Brain Derived Neurotrophic Factor), NT-3,NT-4/5. B: neurokines, cytokines, steroid hormones, bFGF, TGFb |
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How is NGF synthesised? |
Originally as ~250aa precursors -> 120aa proteins via lots of cleavage -> dimers ~15kDa that are soluble (important for setting up diffusion gradients) |
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It is important that NGF get their signal to the correct cell, how is this done? |
done by transmembrane receptors. NGF bind to a series of transmembrane tyrosine kinase receptors. |
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What are Trk and what do they do? |
Tyrosine kinase receptors. Used to respond to neurotrophins. Affect neuronal survival and differentiation through signal cascades. Expressed on the outside of the cell so receptor binding can occur. Cysteine-rich domain is the outer cell part. |
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What are the 3 types of Trk receptors, what substances react with them? |
TrkA: NGF and a weak affinity for NT-3 TrkB: BDNF and NT-4 TrkC: NT-3 |
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How many isoforms of TrkA/B/C are there? What causes such isoforms? |
Alternative splicing = isoforms TrkA = 2 TrkB = 4 TrkC = 3 |
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What can truncated forms of Trk be used for? |
to mop up ‘excess; neurotrophins; means more receptors on the surface though not more reaction cascades going on inside of the cell |
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When an NGF dimer binds to a TrkA receptor, what three different pathways are set off? Describe the pathway that leads to cell survival and note what the other two cause. |
P13 kinase pathway: adapter proteins -> P13 kinase -> Akt (or PKB) kinase = cell survival ras pathway & the PLC pathway = neurite outgrowth and neuronal differentiation. |
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If 2 NT3 molcules binds to TrkA on the cell membrane or if 2 NGF molecules binds to it, what will happen? |
NT3 = lead to surface signalling and therefore local axonal growth NGF = cause endocytosis and vesicular transport will occur. This will lead to cell body signalling and therefore survival and differentiation. |
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What is the name of the receptor that leads to cell death? |
P75 - contains type II death domain |
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If a cell only had P75 receptors and it was given NGF, what would happen to the cell? |
Death. Most cells express both types of receptor, but those expressing mostly P75 are going to die. |
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What has to occur for P75 receptor binding to not cause death? Why/when is this feature useful? |
if TrkA is also present then a boost in performance will occur as long as the arms proteins link the two together. Useful for if there are less neurotrophins around. If the arms proteins do not link, then apoptosis can occur. |
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Why do neurons die? |
-Removal of cells that do not have a function anymore (tails) -Cells with an inappropriate phenotype-To help pattern formation or morphogenesis within the body (hand development) -no longer necessary to function (tadpole tails) -killing off infected cells (diseased) |
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Name some neuronal death mechanisms. |
apoptosis, necrosis, autophagy, dark cell death, parapotosis |
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What is necrosis? |
An accidental, pathological injury causing death. A contagious area of cells all response and initiate an immune response. Causes big holes to form in cells and the contents to leak out. This leakage is what causes the immune response. This immune response results in an influx of neuroglia. |
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What are neuroglia? |
Cells found in the CNS or PNS that have four main roles: To surround neurons and hold them in place. To supply nutrients and oxygen to neurons. To insulate one neuron from another. To destroy pathogens and remove dead neurons |
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Describe apoptosis |
sporadic loss of individual cells. As it is a very orderly response there, all the cell contents remain packages up and no immune response is triggered. The cells around it eat up the debris. |
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What is autophagy? |
The cell eats itself – a mechanism that has been occurring more over the past decade or so. |
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Describe dark cell death (DCD)? |
a very specific mechanism that is a feature of Huntington’s Disease |
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What are the features of apoptosis? |
Shrink in size Nuclear chromatins condense (form pynknotic nuclei) Cell membrane stays relatively intact 'Dog paw' shape Blebbing Eventually, the cytoplasm and nucleus make apoptotic bodies which then phagocytose. DNA then has a laddered appearance |
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What are caspases? |
proteins that run apoptotic processes and are central players in this process |
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What is one of the ways that the mitochondria can lead to cell death? |
Death stimulus = caspase 8 = causes the mitochondria to become leaky and Cytochrome C leaks out. In the cytoplasm, there is the formation of the apoptosome (containingCytochrome C, APAF1 and caspase 9) - these chop the DNA into 200 base pair pieces = effector caspases = apoptosis. |
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The mitochondria had a pathway called the junk pathway, what is it and how does it work? |
An independent cell death pathway. Usually BCL2binds to BAX and therefore they stay in the cytoplasm. If BH3 is present, due to a death stimulus, it will bind to BCL2 and BAX will transfer into the cell along with BH3. This will initiate the death response and the mitochondria will become leaky. Jumps straight to the effector caspases part of the cycle. |
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What are the features of necrosis? |
Not an ordered process Initial swelling of cell/nucleus chromatin condenses into small clumps membranes and organelles disintegrates = immune reaction induced/phagocytosis. Fast response to toxic stimuli |
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What are the features of autophagy? |
Formation of autophagic vacuoles, that have very distinct vacuole membranes. Sequestering of organelles to these where the lysosomes degrade them to basic macromolecules Degradation of mitochondria = no more energy = cell dysfunction. |
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What are features of dark cell death? |
Similar to apoptosis - cells condense but no blebs. Not smooth They are then condensed down to the point where they are engulfed. Characteristically seen in patients withHuntington’s Disease |
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What are parapoptosis features? |
Deemed an ‘intermediate’ between apoptosis and necrosis due to its morphology. Requires gene transcription. Caspases are involved but not in the same way as in apoptosis. Some membrane blebbing but also organelle swelling and an inflammatory response is caused. |
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What is the biochemistry of AD? |
Two main ones are: b-amyloid plaques Neurofibrillary tangles that are aggregates of sticky hyperphosphorylated-tau. |
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What is the pathology of AD? |
Mass loss of cells in this disease which are specific to areas of the entorhinal cortex, hippocampus and cerebral cortex. Enlargements of ventricles (fluid filled spaces) |
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What cell death pathway is used in AD? |
Apoptosis and necrosis. |
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What is the biochemistry of Parkinson's? |
The biochemical markers of PD are cytoplasmic protein aggregations, including a-synuclein, which form Lewy bodies. |
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What is the pathology of Parkinson's? |
There is a mass loss of primarily dopaminergic midbrain neurons, especially in the substantia nigra pars compacta – this causes a limited production of dopamine. |
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What is the pathway of cell death in Parkinson's? |
apoptosis and necrosis |
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What is Creutzfeldt-Jakob disease (CJD)? |
A rare and fatal condition that causes brain damage that worsens rapidly over time. Most people die within a year of the symptoms starting. There are different types of CJD, one of them (variant CJD)is caused by eating cow meat that is infected with BSE (mad cow disease). |
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What is the biochemistry of Creutzfeldt-Jakob disease (CJD)? |
activity and accumulation of prion protein |
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What is the pathology of Creutzfeldt-Jakob disease (CJD)? |
Pathology: widespread cell death throughout the brain |
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What is the cell death pathway of Creutzfeldt-Jakob disease (CJD)? |
Apoptosis and necrosis |
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What are some of the potential symptoms of AD? |
Earliest - repeating conversations/questions Memory problems - going to write something but forgetting before they manage. Names of people/places/faces Later - getting lost, struggling with money, personality changes - hallucinations, paranoia, weight loss, inability to communicate. Often die from pneumonia rather than the disease. |
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Why do the two key biochemical features of AD occur? How does this negatively effect brain function? |
Sticky hyperphosphorylated tau proteins become associated with themicrotubules = neurofibrillary tangles. Eventually disintegrate, limiting cell communication. Amyloid plaques are aresult of b-amyloid build-up. Created from amyloid proteins dividing improperly = astrocytes and microglia react, causing inflammation which isdamaging in itself. |
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Juvenile hitting of PD can occur when and why does this happen? |
before you are 20 due to familial conditions. |
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What symptoms are linked to PD? |
First: Physical symptoms; shaking, jerking muscle movements. Second: Mood, thinking and behavioural changes Last: symptoms linked to the autonomic nervous system(ANS), where processes such as breathing and bowel movements are impaired. |
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Why/how could it be used and what is the problem associated with using NGF as a cure for peripheral nerve damage? |
If cells have enough NGF = survival of cell death process. Cut nerve, put NGF in area than nerve needs to grow to and the nerve will grow towards it. Problem: NGF causes severe pain response. |
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How might NGF help cure AD? But what problem occurred with clinical trials of the cure? |
If cells have enough NGF = survival of cell death process. Did slow/halt disease. Problems: in some patients, NGF leaked from brain into cerebral spinal fluid = intense back pain. Brain fluid system therefore must be leaky. |
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How were the problems associated with the use of NGF as a cure to AD overcome? What results has this method found? |
Less quantity (a more natural conc) used More localised to specific areas Looking promising in animal studies and early clinical trials! |
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What substance could potentially be used for curing Parkinson's and why? |
GDNF = is a potent neurotrophin for midbrain dopaminergic neurons and are lost in patients who have Parkinson’s disease, therefore could serve a potential role in neuroprotection for it. |
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What trials have been done on potential treatments for Parkinson's. How did they make an error in subsequent trials? |
GDNF injection trials: promising results in decreasing motor control symptoms, halting progression of the symptoms and even making them better. It has been shown to keep neurons alive and also encourage them to spread out new processes. Control trial: GDNF did not improveParkinson’s symptoms - potentially because the area of the brain that it was injected into was changed from the first trial |
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What potential problems might have been found with using GDNF as a treatment for PD? |
In the bodies of some given the treatment, GDNF antibodies were found, suggesting that GDNF leaks either due to a leaky membrane or because of how the GDNF is inserted into patients |
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What is leptin? Why is it linked to Alzheimer's? |
A naturally occurring anti-obesity hormone - also found to prevent neuronal death. Prevents up regulation of biomarkers linked to AD. Blood of those with Alzheimer’s have been found to have decreased levels of leptin |
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How might leptin be linked to a treatment of AD? What problems are there with this treatment? |
As those with AD have decreased leptin levels, raising them again might help. Problems: have to inject intravenously – old people on along term drip every week or so is not practical so have to try and use a pill but this is more complex. Leptin has also been found to cross the blood brain barrier |
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What is homocysteine ? |
A natural bi-product of the SAMe cycle, usually removed by the kidneys or recycled. |
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How is homocysteine linked to AD? |
If levels of this are elevated = doubles risk of AD - lack of co-factors = folate = more tau and homocysteine = sticky hyperphosphorylated-tau. - been found that one of homocysteine’s breakdown products, homocyctemic acid, increases amyloid beta expression. - been found to stop cells from putting out processes. Reduces cell flexibility to repair. - activates neuro inflammation |
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How might B vitamins be used to help treat AD? What are the problems with this treatment? |
Identify patients with elevated homocysteine levels, give them B vitamins which help recycle it. - if AD is found in a patient, it is likely that it will already be too late to give them B vitamins as they aren't routinely screened for. Unless a health care programme is created that does this, it is hard to tell whether B vitamins are an effective preventative measure. |
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How might anti-inflammatory drugs help treat AD? |
Anti-inflammatory drugs potentially could block the inflammations of the brain linked to AD. It blocks production of nitric oxide – nitric oxide can kill cells can, stop them from communicating correctly and make their proteins sticky. |
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What study was done that is promising to the use of anti-inflammatory drugs as a treatment for AD? |
Scandinavian countries where you can’t get these drugs without prescription means you can track those who have taken them. People who’ve taken non-steroidal anti-inflammatory drugs at the age of 70-75 have lower rate ofAlzheimer’s |
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What problems are there with anti-inflammatories as a realistic treatment for AD? |
Don’t reduce it, just delay it– rates of Alzheimer’s do catch up in the next 10 years to the levels they would normally be at anyway. Can damage small blood vessels and leave micro-bleeds in the brain |
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What general reasons are there for the cures of neurological diseases not working? |
Psychopharmacological reason: blood brain barrier very hard to get through Inefficiency of animal modelling: most animal models perform acute, sudden loss of certain neurons, not relatable to humans. Also, give drugs to animal at the time the neurons are dying, by the time a human will get to a clinic, a lot of the cells are already dead. |
