Small molecule may play big role in Alzheimer’s disease

Feature | August 8, 2012 | By Aaron Dubrow

Image of aggregation mechanism of Aβ42 protein, which plays a major role in Alzheimer's disease, in the absence or presence of the inhibitor Aβ(39-42).

Amyloid β-protein (Aβ) plays a significant role in Alzheimer's disease. Certain C-terminal fragments (CTFs) have been shown to be effective inhibitors of Aβ42, a form of the amyloid protein. Here we see the aggregation mechanism of Aβ42 in the absence or presence of the inhibitor Aβ(39-42). Normally Aβ42 forms soluble, neurotoxic oligomers before forming larger, fibrillar structures. Aβ(39-42) binds directly to Aβ42 monomer and oligomeric species and eliminates the formation of large Aβ42 oligomers, driving the formation of nontoxic oligomeric species which also eventually form fibrils. Above image courtesy TACC.

Front page image of PET scan of human brain with Alzheimer's disease courtesy Wikimedia Commons.

Alzheimer's disease is one of the most dreaded illnesses facing older Americans, but there is no consensus on the underlying mechanism of the disease.

A team of researchers is using powerful computer simulations to explore the hypothesis that toxicity in the brain is caused by small and transient molecules, and has found new ways to inhibit their formation.

"We don't know what the problem is in terms of toxicity," said Joan-Emma Shea, professor of chemistry and biochemistry at the University of California, Santa Barbara, (UCSB). "This makes the disease difficult to cure."

Since 2007, Shea has run thousands of simulations of amyloid peptides using the Rangersupercomputer at the Texas Advanced Computing Center (TACC) to better understand the structure, formation, and behavior of amyloid accumulations.

“We can identify the important structures that are adopted by [amyloid] peptides at a resolution that exceeds what can be done experimentally," she said. "This helps us understand what structures lead to a self-assembly."

Accumulations of amyloid plaques have long been associated with the disease and were presumed to be its cause. These long knotty fibrils form from ‘misfolded’ protein fragments, and are almost always found in the brains of diseased patients. Because of their ubiquity, amyloid fibrils were considered a potential source of the toxicity that causes cell death in the brain. However, the quantity of fibrils does not correspond with the degree of dementia and other symptoms. Increasingly researchers are looking at small, soluble precursor forms of the fibrils, known as oligomers.

"These are difficult to detect experimentally because they tend to be transient species," Shea said. "There's no consensus on how big they are. There are still a lot of debates."

Shea, Michael Bowers, professor of chemistry and biochemistry at UCSB, and a third experimental collaborator, believe the transient oligomers may be responsible for the onset of the disease through interactions with the cell membrane.

"These oligomers may be toxic by inserting themselves into membranes and causing damage to the membrane," Shea said. "The membrane is critical for the cell viability."

In 2007, Shea and Bowers received a grant from the National Institutes of Health to investigate this theory. Together, they have spent the last five years looking at small peptide-based inhibitors that would prevent these oligomers from forming.

"If you can prevent the oligomers from forming, you can limit toxicity," Shea said.

A paper in the November 2011 edition of Biochemistry, co-authored with the Bowers group, described how a class of small molecules known as c-terminal inhibitors stopped the formation of oligomers, possibly halting disease progression before it is too late.

"Shea's simulations put a molecular face on the cross sections and oligomer distributions that we experimentally measure," said Bowers. "Of significant importance is the simulation of the ABeta42 monomer structure that very nicely correlated with our experiments. Also of importance are calculations on the sites and mechanism of attachment of potential therapeutic agents that we are testing as ABeta aggregation inhibitors."

Simulations on TACC’s Ranger and Lonestar high-performance computers helped researchers identify where the inhibitors bind and led to new ideas about how inhibition can be improved.

The projects have required more than 13 million hours of compute time since 2009.

"The number of atoms is huge—we need a lot of computational resources to simulate them. Nothing that we're doing here is something that we could do on our home clusters. The scale of it is intractable," Shea said.

Ranger and Lonestar are part of the Extreme Science and Engineering Discovery Environment (XSEDE), the NSF-funded effort to provide e-infrastructure and computing power to US scientists.

"With growing computational resources and capabilities, we'll be able to look at how these proteins interact with membranes," Shea said. "We're far away from simulating a whole cell, but we can start incorporating additional elements that may turn out to be important."

About the Author

Aaron Dubrow

Science and Technology Writer, Texas Advanced Computing Center

Comments

Add New Comment

by Anonymous | April 22, 2013 - 11:03pm

Great Share! You made some

Great Share! You made some decent points there. I looked on the internet for the issue and found most individuals will go along with with your website.bli lång

by Anonymous | April 22, 2013 - 6:21am

Campbell Green

I like the blog. I believe this will be helpful in the future…

iPhone App Development

by Anonymous | April 20, 2013 - 9:39am

Matt Hunn

I am really impressed from your immaginative thinking and impressive stated information..Matt Hunn

by Anonymous | April 20, 2013 - 9:37am

You may write about the

You may write about the resources on the blog. You could reference it's flawless. Your blog rating could escalate your bottom line.Industrial Supply

by Anonymous | April 17, 2013 - 5:26am

su

I really like your Blog, its very informative. su deposu

by Anonymous | April 17, 2013 - 2:02am

It is a nice article. This

It is a nice article. This site has lots of advantage.Binäre Broker

by Anonymous | April 6, 2013 - 8:17am

Hello! I just wish to give an

Hello! I just wish to give an enormous thumbs up for the nice info you've got right here on this post.¿Qué son las opciones binarias?

by Anonymous | April 2, 2013 - 9:36am

beton

It seems too complex and extremely broad for me. beton delme

by Anonymous | April 5, 2013 - 11:22am

Bookmark your site

Thank you pertaining to giving this excellent content on your web-site. I discovered it on google. I may check back again if you publish extra articles.. - Semarang Hotel

by Anonymous | March 28, 2013 - 6:20am

Nice information, many thanks

Nice information, many thanks to the author. It is incomprehensible to me now, but in general, the usefulness and significance is overwhelming. Thanks again and good luck!

Facebook Applications Development

by Anonymous | March 26, 2013 - 10:12am

Such an Excellent post.I am

Such an Excellent post.I am inspired with this blog, I always found some great information on this blog.a knockout post

by Anonymous | March 26, 2013 - 1:57am

I was so lucky to visit this

I was so lucky to visit this site I really want to recommend this to everyone cause there is no doubt about its content I really love this one thanks for sharing this!lofts converters

by Anonymous | March 26, 2013 - 1:52am

Such an Excellent post.I am

Such an Excellent post.I am inspired with this blog, I always found some great information on this blog.buy beeswax

by Anonymous | March 25, 2013 - 8:21am

Branded Logos

Really your post is really very good and I appreciate it. It’s hard to sort the good from the bad sometimes, but I think you’ve nailed it. You write very well which is amazing. I really impressed by your post.

Branded Logos

by Anonymous | March 21, 2013 - 7:38am

Logo Design

Thank you so much for writing a lot of this good information! I am looking forward to reading more.
Logo Design

by Anonymous | March 21, 2013 - 4:53am

HI

Wow. This blog is truly a gold mine. I have been wallowing on this for quite sometime and here I am reading about it! I will actually try these tips and let you know how they work out! Thanks again mate.
quick loan

by Anonymous | March 20, 2013 - 5:08am

iPhone Application Development

Nice information, many thanks to the author. It is incomprehensible to me now, but in general, the usefulness and significance is overwhelming. Thanks again and good luck!

iPhone Application Development

by Anonymous | March 20, 2013 - 1:59am

Incorporating Incorporating is one of the best ways a business

Incorporating is one of the best ways a business owner can protect his or her personal assets. Most people choose to incorporate solely for this reason, but there are other advantages as well. For example, the corporate business structure saves you money in taxes, provides greater business flexibility, avoids audit chances, better itemization and lets you more easily raise capital.
incorporate

by Anonymous | March 19, 2013 - 4:27am

HI

“Hello! I could have sworn Ive been to this weblog before but soon after browsing by way of some of the post I realized it is new to me. Anyways, Im certainly happy I discovered it and Ill be book-marking and checking back often!”
I thought about this

by Anonymous | March 19, 2013 - 10:34pm

check out the post right here

I do wish there were more people like you around on the interwebs. Thank you for the great article I did enjoyed reading it, You're so cool! I don't think I've read anything like this before. So good to find somebody with some original thoughts on this subject. Thanks for starting this up. - selimut murah

by ZoeLouella | March 13, 2013 - 2:26am

All i can say about this

All i can say about this website is awesome thanks man i believe you rich your goal thanks for this site фотошоп

by Anonymous | March 20, 2013 - 10:17pm

Also of importance are

Also of importance are calculations on the sites and mechanism of attachment of potential therapeutic agents that we are testing as ABeta aggregation inhibitors.bordeaux restaurant

by Anonymous | April 22, 2013 - 7:32am

OASIS is a massive virtual

OASIS is a massive virtual galaxy where your avatar can be anything you want it to be, it's a place where you can live, play, quest on any of the thousands of planets.
vancouver web design

by Anonymous | March 13, 2013 - 8:50pm

Like website, and look

Like website, and look forward to your update new article, I will often come to visit! here link

by Anonymous | March 5, 2013 - 10:12am

I would be very thankful if

I would be very thankful if you continue with quality what you are serving right now with your blog..Skoinlägg

by Anonymous | March 5, 2013 - 8:03am

hi

by Anonymous | March 5, 2013 - 7:59am

hi

Things are very open and intensely clear explanation of issues. was truly information. Your website is very beneficial. Appreciate your sharing.
pure garcinia cambogia

by Anonymous | March 5, 2013 - 7:55am

hi

I’m glad Yahoo pointed me to it. I was able to get the know-how I was searching so badly for days now.Thank You very much for your really good web page. Have a good day.It's very useful for everyone for sure.
travel agent Sydney

by Anonymous | March 4, 2013 - 1:15pm

I would like to appreciate

I would like to appreciate your hard work you did write this post, Thanks for sharing this valuable post.
Free Stuff Online visit here

by Anonymous | March 3, 2013 - 9:55am

Kiiwo

I am in the middle of working on a school report on this topic and your post has helped me with the information I needed to complete it. Thanks Kiiwo

by Anonymous | March 2, 2013 - 3:31am

hi

OASIS is a massive virtual galaxy where your avatar can be anything you want it to be, it's a place where you can live, play, quest on any of the thousands of planets.
instagram likes app

by Anonymous | February 28, 2013 - 6:43am

cabin

Do you have any other posts about this topic.
hacamat
catering
gelinlik modelleri
carpet
prekast

by Anonymous | March 1, 2013 - 11:59pm

discover this info here

You're so cool! I don't think I've read anything like this before. So good to find somebody with some original thoughts on this subject. Thanks for starting this up. - florist di semarang

by Anonymous | February 26, 2013 - 4:52pm

hi

Our posting should be related to the topic "Do you have any other posts about this topic.
netticasino

by Anonymous | February 22, 2013 - 1:37pm

fe

i want to have web master make web site and seo
seo
kurumsal seo
web tasarım
seo

by Anonymous | February 18, 2013 - 9:54am

Accumulations of amyloid

Accumulations of amyloid plaques have long been associated with the disease and were presumed katalog stron to be its cause. These long knotty fibrils form from ‘misfolded’ protein fragments, and are almost always found in the brains of diseased patients. Because of their ubiquity, zdrowie i uroda amyloid fibrils were considered a potential source of the toxicity that causes cell death in the brain. However, the quantity produkcja przemysłowa
of fibrils does not correspond with the degree of dementia and other symptoms. Increasingly researchers marketing are looking at small, prawo i społeczeństwo soluble precursor forms of the fibrils, known as oligomers.
Usługi transportowe Wrocław
AGD i RTV
dom
edukacja
internet i komputery
kultura i sztuka

by Anonymous | February 14, 2013 - 12:41pm

Mo Lewis of the Wholesale Snapback Hats Jets sheared a blood MLB Snapback Hats vessel in Bledsoe’s NFL Snapback Hats chest, causing Bledsoe to NBA Snapback Hats wait seven weeks before Obey Snapback Hats getting medical clearance. By Ymcmb Snapback then, too late. Bill Belichick Beanie Hats and the Patriots were NBA Beanie Hats sold on Brady. Belichick MLB Beanie Hats went to Bledsoe and NFL beanie Hats said, “I’m sticking with NHL Beanie Hats the kid. But stay ready, just in case.” The team Obey Beanie Hats was winning and the coach followed Supreme Beanie Hats his gut, much like YMCMB Beanie Hats Jim Harbaugh with Kaepernick. There’s a Armani Beanies Hats difference, though.

by Anonymous | January 28, 2013 - 12:11pm

Primary links

Small molecule may play big role in Alzheimer’s disease

About the Author

Comments

Post new comment

Careers

Digital Stream

Calendar

Upcoming

Topic Tags

Supported By