The insidious beta-amyloid

First of all, thank you for all your feedback and constructive criticism. I aim to incorporate those into my writing and hopefully continue to make the writing both informative and devoid of too much neuroscience jargon.

One of the post-mortem hallmarks of Alzheimer's disease is the presence of amyloid plaques (also called senile plaques, neuritic plaques, etc.). For over 3 decades, researchers have been trying to understand what these plaques are made of, and how they contribute to the pathology of Alzheimer's Disease.

Today's blog post will explore questions about these plaques and their insidious component - beta-amyloid.

What are plaques made of?

Plaque usually means "sticky material.". Amyloid plaque is made of oligomerized beta-amyloid strands. That is just a fancy way of saying - a bunch of beta-amyloid stuck together.

What is beta-amyloid?

It's a short fragment of a larger protein, which is potentially toxic in Alzheimer's Disease.

What causes this beta-amyloid to stick together?

Bits of beta-amyloid clump together due to certain chemical properties that each strand has. An easy analogy is if you have a dog, you know that dog hair tends to clump together (and form, what my roommate calls 'bales' of hair). So, essentially, these bits of beta-amyloid clump together and form larger bits of beta-amyloid, which, in turn, form the larger plaque.

Dog hair - in case you're like my mom and hate dogs (and have therefore never seen it clump together). Love you, momsie!

What causes the singular beta-amyloid to form in the first place?

Beta-amyloid is cut out from a larger parent protein called Amyloid Precursor Protein (APP).

Why is APP being cut in the first place? Why not just get rid of it entirely?

When APP is cut in the 'right' way, fragments are made which are important to normal processes of the neuron. Therefore, getting rid of it entirely (even if we could it) would have deleterious effects on the normal function of neurons.

What cuts the amyloid-beta fragment out of APP?

There are enzymes in cells that play a variety of functions. A few enzymes are capable of cutting APP at distinct spots, releasing fragments of differing lengths. In this figure below, the blue fragment is the APP protein, and the little green fragment is the harmful beta-amyloid fragment. The scissors, represent 2 enzymes that cut it out.

Cleavage of APP by enzymes (Credit - McGill University)

An analogy might help here. If you consider APP to be a long string in length, depending on where along the string two sequential cuts are made, you would get fragments of differing lengths. The length of these fragments are crucial - because they determine whether beta-amyloid will form, or other largely non-toxic fragments are formed.

Okay, this is getting complicated, give me a summary, Nipun

Amyloid plaque is composed of beta-amyloid fragments. These fragments are cut out of a larger protein called APP by certain enzymes.

What does amyloid plaque do? 

This is where the story gets interesting (note: whenever a scientist says "interesting", he/she means - "controversial").

Let's take the traditional position first. Many believe that amyloid plaque disrupts normal cellular function and this leads to cell death. How? Well, it's possible that this plaque inserts into the cell membrane disrupting the balance of electric charge between the inside and outside of the cell.

Or, amyloid plaque may activate reactions inside the neuron that lead to it's death. Imagine the cell as your apartment, and a receptor (refer to post #1 for a better understanding of a receptor) as your doorbell. Normally, when someone rings your doorbell, you look through your peep-hole, see that it's your boyfriend/girlfriend, and all is well. In your neurons this is a normal, beneficial protein binding to the receptor and saying, "Okay this is business as usual, carry on."

But, imagine if the doorbell rang, and you realized this was at your door ---

(Insidious Donald Trump = insidious a-beta. Photo credit - greenrushinvestors.com)

That face would send anyone into a frenzy. You might even consider blowing up your own house, just so you don't have to interact with THAT HAIR. Well, that's what the cell decides to do - it sees beta-amyloid and decides to shut down shop to protect other cells nearby.

Or, it may attract the attention of your immune system which would, in turn, lead to more of the aforementioned Donald Trump effects. (If only there was an immune system that would take out the trash that is Donald Trump, amirite?)

FYI - Fellow grad students, check out Sakono and Zako (2010) for a review on A-beta formation (http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2010.07568.x/epdf), if you want to read more.

So, what's the controversy?

Well, you see, there are those who believe that beta-amyloid has nothing to do with causing the disease at all. They believe, that this beta-amyloid is a consequence of the disease, not a cause of it. You know - what came first, the chicken or the egg*?

The chicken or the egg* (Image credit: The Guardian)

Is there any evidence to support this? Actually, yes. You see, there are patients who have normal levels of plaques, but advanced Alzheimer's Disease. As a corollary, there are those who have amyloid plaque hallmarks in their brain (post-mortem), but never showed the cognitive decline correlated with Alzheimer's Disease.

Why do we care? Why not just try to treat it anyway?

If amyloid plaque comes after whatever is causing the disease, reducing levels of plaque would have no impact on the disease. 

Should we waste all that funding (and all those countless graduate student hours) on what is potentially a dead end?

YES! Along with the topic of tau tangles (next week's post), Amyloid plaque is our best target for the treatment of Alzheimer's. Plus, there is some promising clinical data that suggests that reducing amyloid levels results in improved cognition. 

What's your opinion, Nipun, Mr. Neuroscientist?

My opinion is that beta-amyloid plays a causative role (along with tau) in Alzheimer's Disease, and is therefore a part of the puzzle. And, therefore, warrants further understanding.

My head is reeling, Nipun, this was supposed to be simple. Summarize this shit and let me go.

Fair enough. Here's the gist. Beta-amyloid is likely to be harmful for neurons. And, likely to be one of the underlying causes of Alzheimer's Disease. And, is therefore a target for drug therapies for treating this disorder.

Follow the blog on twitter at @AlzBlog101, and me on twitter at @NipunChopra7. Let me know what made sense/what didn't. What you liked, what you didn't. All that good stuff. Thanks for reading! Thank you to Emily Neitzel (@EmilyNeitzel) for editing this post.

*It is logically congruent that the egg came first. Because, the species from which chickens evolved, laid an egg, which was the very first chicken. Think about it. Therefore, the egg came first (because it's parent was chicken-like, but not quite a chicken).