BMS3021 Lecture 15 Alzheimer's disease

describe alzheimers: what is it, chacteristic pathology, symptoms, onset, disease transmission

alzheimers is the most common neurodegenerative disease. it is characterised by the aggregation of unfolded proteins to either result in amyloid plaques of amyloid AB protein (extracellular) or neurofibrillary tangles (intracellular) of hyperphosphorylated tau proteins. resultantly (through a mechanism which is unclear) there is neuronal destruction, a disruption in neuron communication, neuron metabolism and neuron repair. moreover, we observe reduction in brain size and a reduction in glucose usage in neurons. the disease manifests by dementia and tends to onset late in life sporadically (not a strong genetic component)

describe amyloid plaque accumulation in alzheimers

beta amyloid plaques are dense deposits of protein and cellular material that accumulates outside and around nerve cells. these are produced from the amyloid precursor protein (APP) - a transmembrane protein with an extracellular domain. APP is cleaved by three classes of secretases. which enzyme is dominant will determine what amyloid Beta is produced. *alpha secretase:* 1. alpha secretase cuts at residue 17 of the Abeta (amyloid beta) protein, releasing part fo the extracellular domain of the APP protein which is non toxic (sAPPalpha) 2. gamma secretase cut the transmembrane APP protein at around 40-42 of the AB protein. 3. AB (17-40/42) protein will be released. *beta secretase*: very similar process 1. B secretase cuts at residue 1 of the APP, releasing sAPPbeta 2. gamma secretase cut at residue 40/42 (as usual) 3. AB (1-40/42) protein released which is toxic. 4. AB (1-40/42) forms fibrils due to interactions between their C terminal hydrophobic ends. this occurs via a "nucleated growth mechanism". this is where we have a lag phase, then an elongation phase in the formation of beta sheets.

of the products produced beta secretase, which one is more toxic and why

beta secretase (with gamma secretase) will produce either AB 1-40 or AB 1-42 depending on where the gamma secretase cuts. the AB 1-42 is more aggregation prone due to having two extra hydrophobic residues (isoleucine and alanine). the oligomers that are formed cause active destruction of nerve cells.

how is Amyloid beta protein aggregation treated

either: - prevent amyloid beta plaque formation by inhibiting gamma and beta secretase or activating alpha secretase. - using extracellular antibodies against the aggregate to cause it to be sequestered or prevent their elongation

describe the morphology of tau proteins in alzheimers patients

hyperphosphorylated tau proteins form neurofibrillary tangles which are twisted fibres that build up inside the nerve cell

describe the the function of tau in normal individuals, how is their activity regulated

in healthy individuals tau proteins bind to microtubules (stabilising them) through their R domains and acidic residues. the binding of tau proteins to microtubules is decreased when kinases phosphorylate tau because phosphorylation affects the charge of the protein. where as their activity is increased when phosphatases dephosphorylate tau.

other than the toxic effects of amyloid plaques themselves how does dysregulation of amlyoid precursor protein affect the body

the amyloid precursor protein is a metalloprotein and so we get metal ion dyshomeostasis

describe the deregulation of tau in alzheimers patients, how does knowledge of this impact on therapy for alzheimers

when tau phosphorylation is deregulated due to an imbalance of kinase and phosphatases it can become hyperphosphorylated and detatch from the microtubules. we get these amyloid-like structures inside the cell which are made up of tau. when tau falls off it no longer stabilises the microtubules. this means the microtubules cannot allow axonal transport of organelles along neurons. the combined effect is to starve dendrities from the contents of cargo vesicles. autophagy is perturbed resulting in neuronal swelling and inflammation. consequently, therapeutic efforts are targeted at preventing tau hyper phosphorylation and stabilising microtubules