Aducanumab update

Recent work (Sevigny et al (2016)) has been making the rounds on social media. I have seen exaggerated headlines such as "New drug that halts mental decline.." and "A cure for Alzheimer's" making the rounds.

So, what's the dealio, yo? Have we done it? Have we cured Alzheimer's? Let's get into the facts here ---

1. What's this drug called?
Aducanumab - it's marketed by Biogen.

2. How does it work?
This is a drug that targets aggregated beta-amyloid. (Click here for my review on amyloid).

3. How is it different from other drugs that have been tried?
Well, for one, it isn't a "drug" per se. It is an antibody which targets the aggregated beta-amyloid.

4. What's an antibody?
An antibody is something all our immune systems generate to fight off infection. Think of it as your Superman to a Lex Luther. An antibody's role is to identify bad stuff, bind to it, and neutralize it's threat.

Up, up and antibodyyyyy (I'll show myself out)

5. Okay, so what did the study find?

The study found that in one year, patients who were given aducanumab showed less of the amyloid burden than placebo (not given the antibody). And, rather excitingly, this was a dose-dependent effect.

6. What's a dose-dependent effect?

It's a fancy way of saying, the greater the amount of aducanumab given, the better the patients seemed to do.

7. What did they measure?

They looked at amyloid in the brain as well as behavioral symptoms. Both improved dose-dependently with aducanumab.

8. Does this mean anyone suffering from Alzheimer's would benefit from this drug?

Not quite. The effects seemed most pronounced in those who were in early stages of AD?

9. Is this a cure for AD?

Too early to say. The sample size of this drug trial was small. Biogen is currently conducting Phase III drug trials (~1500 patients). Those results will become available in 2021. Also, important to note that the effect was in early stages of AD. 

10. Why the hesitation, bro?

We have been here before. other drugs showed promise in Phase I/II trials only to show no effect in larger trials. Also, don't call me bro, bro.

11. So what's the takeaway?

Very promising data. But, if someone tells you that "they found a cure for Alzheimer's", tell them that statement is still premature.

Day 3 - MicroRNA Monday

Usually Mondays are the worst. But, not today!! It's SFN!!!

There were quite a few microRNA posters I attended today. In case you might not know what they are, here's a quick synopsis of what microRNA are --

microRNA (miRNA) are short strands of RNA that modulate protein expression. To give you an analogy if proteins are lights in a room, miRNA are the dimmer switch. They don't turn the light on or off, but they help ensure that the light isn't too bright, or too dim. 

Here were the highlights of today's events ---

Morning session

1. Minano-Molina (C45) - Found that miR-92-3p, miR-181c-5p, miR-210-3p modulation in Alzheimer's transgenic mice.

2. Edler (C20) - Abeta and tau pathology increases with age in chimpanzees. Studies in primates are becoming rare - for ethical reasons. This study was done with primate brains donated by zoos and research institutions.

3. Bicca (C20) - TRPA1 levels in AD mice are changed - possibly via a response to oxidative stress.

4. DeVito (Z26) - This was my favorite poster of the day. 142-3p involvement in a mouse model of Multiple Sclerosis. They found that 142-3p knockout mice show reduced symptoms associated with the mouse model of MS. The target for this miRNA was the mRNA coding for GLAST (glutamate aspartate transporter). They also found that anti-miR-132 - administered via an osmotic mini pump) help reduce symptoms in the MS mouse. I enjoyed that their group covered the miRNA work from basic, in vitro predictions, all the way to in vivo administration of the miRNA. 

Lunch -

None. Not happy about it. Still.

Afternoon session

I presented my poster all afternoon. It was D25 - microRNA298 -  a dual regulator of proteins involved in Alzheimer's Disease.

SFN Banter

Met some people I have been interacting with on twitter. Remembered that I am incredibly socially awkward in large groups. Also, very jealous of those people who are able to walk up to strangers and engage them in conversation. You know - extroverts.

What did you enjoy about your Monday at SFN?

Day 2 of SFN - Crashing helmets on Stampede Sunday

Stampede Sunday, as I like to call it, was as packed as it is each year. 

There was lots of cool science to talk about and cool scientists to talk about it with. Here with the highlights ---

1. Hendrix (DD56) – Her aim was to raise awareness for her local “brain awareness day”. She was able to do by promoting via social media and designing flyers. She also talked about having visited Capitol Hill and talking to policy-makers about the changing funding climate. Basically, Ms. Hendrix is an advocate for both neuroscience and neuroscientists. We need more people like her. Follow her @RDHendrix.

2. Brager (DD38) – a fellow blogger, her poster showed that cryotherapy increases both the amount as well as the quality of sleep in athletes. Sleep remains an underappreciated area of neuroscience and I saw some other cool work looking at sleep disruption in rodent models. Brager’s work was particularly fascinating because it was in athletes; something many of us ex-athletes can appreciate. Basically - those ice baths are really, really important for recovery. And, if possible, a cryo chambers is even better. 

3. Whitesall (D31) – Working at the Allen Institute, Ms. Whitesall’s work looked at Default Mode Network (DMN) in the mouse brain. In recent years, the idea of the Default Mode – essentially, the baseline of your brain activity – has become apparent. It makes for both interesting science, as well as interesting science fiction. Whitesall’s work hypothesizes that the brain regions comprising the DMN may be one of the first to perturbed in Alzhiemer’s Disease. She will test whether this is true in an AD transgenic mouse line.

4. Kawarabayashi – Looking at tg mice models, they found that PrPc, Abeta mono and dimers, Fyn, NMDA, GSK3beta and pTau all localized in lipid rafts! This ties in both the possible involvement of lipid rafts in AD, as well as seemed to support the amyloid hypothesis.

5. Graham (C87) – Western diet in APP/PS1 mice increases A-beta load and TREM2 activation. TREM2 is the new baby in the AD field, and there will be a lot of work on it. And, as for western diet, STOP BEING SUCH FATTIES, YOU GUYS. And, by you, i mean, me.

6. Brkic (C86) – Omega-3-Fatty Acids have beneficial effects on brain of AD mice – by reducing amyloid plaque burden. There was recently a longitudinal study that determined that fish oil showed no benefit for cognition in AD patients. Brkic informed me that she thought that study was done with patients who has advanced AD, and therefore, an amelioration of symptoms would have been lost in the noise of progressed neurodegeneration. I agree with her. Most AD therapies should be looking at helping decelerate the pathology in mild cognitive impairment patients, in my opinion.

7. Colello (C91) – This was my favorite poster of the day. Their group decided to address the issue of the g-forces experienced by helmet to helmet collisions in football players. They posit doing so by placing repulsive magnets in the helmet of players. This would lead to the generation of a repulsive force that would reduce the g-forces. Their proof of concept suggests that they are able to reduce g-forces (measured by accelerometers) in a rig where they are essentially crashing two helmets together. This is fascinating work! And, a perfect example of how invention often come from people who cross disciplines.

Lunch

All the places close by were closed! Stampede Sunday is the worst. I ate a sandwich from a grocery store. It was awful.

Afternoon sesh

I spent the entire time presenting the boss-man's poster.

What were your highlights from today? My poster is tomorrow (Afternoon session, D25). Stop by and say hi!

Day 0 - Arriving in Chicago

My lab-mate, Baindu and I left Indianapolis about 4PM and, on our way, Baindu introduced me to some new Justin Beiber music. Yes, I listened to Justin Beiber. Does that make me a Belieber? Speaking of music, Beach House's new album just dropped today. If you haven't listened to Beach House before, do yourself a favor and check them out. Start with the album "Bloom".

We got to Chicago just in time for stand still traffic. We drove past McCormick Place on our way to our hotel, and we marveled at the size of it. After navigating the insane traffic, we checked into our hotel, only to find out that wi-fi isn't free.

In 2015.

It's 2015.

Wi-fi should be free.

In 2015.

So, here I am, in the lobby of our hotel, where fellow neuroscientists sit around me - complaining about the lack of Wi-Fi. Also, it's 2015.

I'm really looking forward to tomorrow. The day will start early , and I'll plan on getting to the conference about 8AM. No, I'm not an over-achiever; I just want to squeeze in a professional session before I watch soccer on my computer from 9AM-11AM.

You know, using the free wi-fi that McCormick Place provides.

After that, I'm going to shuffle between a few Nanosymposia on Alzheimer's Disease: Experimental therapies, and a few interesting posters on TBI and AD.

What are you guys going to visit tomorrow?

The tangles of tau - breaking down highways

In a stereotypical brain from an Alzheimer's patient, there is the presence of amyloid plaque and tau tangles. We have already covered amyloid deposits in a previous post. Today, we will be discussing this tau thing. What is it? And, what the heck does it have to do with Alzheimer's Disease?

What is the link between Alzheimer's Disease and tau protein?

Post-mortem brains from Alzheimer's patients often have tau tangles (also called neurofibrillary tangles. The pictures below shows a magnified version of what these tangles look like (tau tangles are on the right, amyloid deposits on the left).

Image taken from bigthink.com

What are tau tangles aka neurofibrillary tangles?

These tangles are composed of a bunch of abnormal tau protein stuck together.

What is tau? why does it clump together during Alzheimer's Disease?

In order to answer this question, I think we should first go over what microtubules are. Microtubules allow the transport of materials across the neurons.

Here is an analogy - if your neuron is a city, then microtubules are the roads. You see, your neuron is constantly making stuff that it needs to send to different parts of the cell. One way to do that would be to simply make something and let it diffuse through the cell. But, this would not be very efficient. Therefore, the cell sets up it's own roadways in order to keep delivery organized and efficient.

Here's the really neat thing. These roadways are entirely dynamic! If the cell is done sending one protein to one part of the cell, it can send workers to that road and break down that roadway.

From Nature Reviews

And this is where tau becomes important. You see, what tau does, it helps the workers know whether or not to break a highway down. Sort of like a beacon to say - this road needs to stay!

Microtubules - the roadway of cells. (Image taken from absoluterights.com)

What happens to tau in AD?

Tau gets hyperphosphorylated in AD.

Wait, stop using big words, you showoff. What does that 'phosphorylation' mean?

Phosphorylation occurs when a phosphate group is thrown onto a protein.

Every protein in every cell of your body is under tight control. This is because, evolution has ensured that every protein can be made, destroyed or made to disappear as the cell needs it. Phosphorylation is one of these regulatory processes. By throwing a phosphate group onto a protein, you can change what that protein is doing.

Okay, what does phosphorylation do to tau?

Well, here's the weird thing about tau, it can exist in three forms---

1. Unphosphorylated - this is the form we have been talking about - when this form is present, the cell knows that that roadway needs to stay.

2. Phosphorylated - This is the green signal for the roadway to be taken apart. Let me reiterate, that this is normal. This phosphorylation-unphosphorylation allows the dynamic rearrangement of the roads in the cell.

3. Hyperphosphorylated - This is bad news bears. This is when the tau starts to misbehave and clumps together.

Okay, this is getting too sciency again. What are you even talking about?

Here's the gist so far - Tau is important to maintain normal function in the cell. During Alzheimer's this protein gets too many phosphate groups put on it. This makes the cell lose a bunch of it's roadways for no good reason.

And, what's worse is that all that hyperphosphorylated tau starts to clump together and form those aforementioned tau tangles.

What do these tau tangles do that's so bad?

Just like the amyloid plaque story, this isn't so cut and dry. Many believe that these deposits lead downstream to neuronal death. And, as we've discussed earlier, neuronal death is a key component of the cognitive issues in Alzheimer's Disease.

Is there a link between this tau stuff and the a-beta stuff?

Yes, there have been many studies that show that a-beta can actually lead to tau hyperphosphorylation (the bad version of tau). There are also a small number of studies, that are studying whether the converse is true - that tau can affect a-beta production.

Can we reduce this hyperphosphorylation?

There have been attempts to target the things that regulate the phosphorylation of tau. These have had limited to no success.

Okay, I'm bored. Summarize this.

Okay, here goes. Tau itself is not bad. The neuron needs it. But, for reasons that remain unclear, tau converts to a form (hyperphosphorylated). And this form arguably leads to cell death. And that, in turn leads to the tau tangles we observe in the brains of Alzheimer's patients.


Let me know what you guys think. Did anything still seem confusing? Please reach out to me at @AlzBlog101 or @NipunChopra7 .

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).

What is Alzheimer's Disease - defining some key terms

Everyone has heard of Alzheimer's Disease. Whether it is because someone you know has suffered from it, have read about it, or are trying to impress a lady with your knowledge of The Notebook (Admit it, gentlemen, we only pretend to enjoy that movie).

But, what exactly is this disorder? We will cover the diagnoses and underlying pathology in future posts. Today, we will focus on a definition of the disease, along with explaining a few key terms that are integral to all future posts.

So, let's get to those key terms. Now, all of you fall under two categories here -- 

1. If you are a neuroscientist, or have taken graduate level biology, most of this might seem redundant to you. But, I would appreciate you reading through this any way, to help critique my explanations and analogies. 

2. If you have always wondered what these terms meant, I hope I can shine a light on their meaning.

Neuron - These are cells in the brain. They are responsible for all your emotions and your memories.  Depending on where in the brain they are located (there are different brain regions responsible for different functions) or what type of neuron is present (there are different types), they contribute to why you think - "Ryan Gosling", every time you hear the word "dreamy". Or, you scrunch your nose, every time someone brings up yogurt (seriously guys, yogurt is disgusting). Neurons are the minions that facilitate everything you consider to be a feeling or a memory. 

In a certain part of the brain, called the Hippocampus, there are neurons that allow for the formation of new memories. During Alzheimer's Disease, this is one of the first regions to be affected. What does it mean to be affected? The neurons in this brain region die. Why is this relevant? Because, unlike cells in other parts of our body, neurons do not divide. Therefore, once a neuron dies, there will not be another one to replace it. And the relevance to memory? Well, theoretically, if you've lost a neuron relevant to a memory, you've lost that memory, or the ability to make a new memory. 

If the brain is an engine, and different areas of the brain represent different engine parts, neurons are the nuts and bolts that enable everything to work. 

Receptor - A gateway for communicating with neurons. Think of the cell as a fortress. A receptor is the draw bridge which allows communication with the fortress. Either by allowing a visitor in, or by relaying the messages of the visitor to the people inside the fortress.

Dementia - This is a loose term that is often misinterpreted. Dementia refers to a state in which normal brain function is impaired. Memory loss (as seen in Alzheimer's) is a subtype of dementia. Alzheimer's Disease represents the most common form of dementia in the adult population.

Memory - What is a memory? The ability to recall something. How are memories made? Well, we have a pretty good idea of the mechanism and brain regions involved. Where are memories stored? We know certain brain regions are important for making memories vs storing memories. Where is the memory of the lyrics to Taylor Swift's album stored? We could figure out the general area by hooking you up to a fancy machine, but here the pictures gets hairy. Suffice to say, memory formation/retrieval/consolidation/storage remain one of the key areas of research in neuroscience. What we do know is that Alzheimer's Disease involves impairment of memory processes.

Neurodegeneration - a process during which neurons progressively continue to die. Much like the progressive collapse of well-set dominoes, once this process starts, neurons continue to die over time, and there is very little (currently) we can do about it. What starts neurodegeneration in Alzheimer's Disease (Or, using our analogy, what pushes the very first domino?) ? We will visit this controversial question in future posts.

So, what is Alzheimer's Disease?

This disease, first characterized by Alois Alzheimer (hence the name) is a disorder in which neurons in key brain regions die. This results in the initial symptoms of memory loss and eventual death. Interestingly, patients of Alzheimer's Disease do not die of the disorder, per se, but it is usually the diseases associated with Alzheimer's (Pneumonia, for example) which is the direct cause of death. 

Alzheimer's Disease is an incredibly prevalent form of dementia in the elderly. And, as our sanitation, medication and standard-of-living continue to improve, the number of people suffering from it is only expected to increase. 

Please let me know if there are specific areas you would like for me to cover. You can reach out to me on twitter at @NipunChopra7.