Several ideas and suggestions have emerged lately to try to explain where APP is cleaved within the cell. It looks like the first cleavage (by Beta secretase) is thought to be mostly at Plasma Membrane although it is known that beta secretase activity in increase in acidic pH's.
Any tips about how this processes are running in the cell?
Inside the cell, APP is frequently cleaved within the membrane micro-domains by Gama-secretase. The initial cleavage by Beta secretase leaves various types of membranously tethered C-terminal fragments, which are later cleaved by the intrinsic activity of PS1 in the gama secretase complex. Although, APP can be enriched in the membranous fraction but APP CTF's are better enriched in detergent insoluble membraneus fraction. The live cell imaging of the cells expressing GFP tagged APP also agree to this notion but to tackle the localization of CTF's produced after cleavage is quite a difficult task. For further information, take a look at the following article.
"Mechanism of Alzheimer Amyloid β-Protein Precursor Localization to Membrane Lipid Rafts"
By Yuhki Saito, Takahide Matsushima and Toshiharu Suzuki
I hope this will be helpful.
While there is a vast literature on APP cleavage by beta and gamma secretases, the studies are mostly performed using non-neuronal cells. What the field has discovered is this: APP processing can occur in just about every intracellular organelle - which doesn't help. What is critical is to understand where these events take place in neurons, especially in the aging brain where a number of dynamic intracellular trafficking steps don't seem to quite work at optimal levels. How synaptic activity influences APP cleavage is equally challenging to address.
There is general agreement that endocytic trafficking is critical for APP processing. However, I wouldn't put too much emphasis on the acidic pH data from in vitro activity experiments because BACE1 undergoes dynamic trafficking through a series of endocytic/recycling organelles, many of which have acidic pH. The key issue is where the enzyme and substrate come together because APP and secretases appear to have their own intracellular itinerary, regulated by shared as well as distinct trafficking regulators. Membrane raft localization of APP secretases introduce yet another level of complexity in the possibility of successful encounter between APP and the secretases.
Don't forget to let me know when you do figure out the answer to your question.
APP processing usually occur in just about every intracellular organelle. But it is difficult to understand in which part of the neurons it occurs especially in the aging brain where a number of intracellular signalling takes place. But as I think its a enzymatic process so the events will takes place in cells.
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