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Alzheimer’s Disease Severity Reduced by Blocking Sugar Binding to the BACE1 Enzyme
scma_2007
Posted: Tuesday, January 27, 2015 6:10 PM
Joined: 9/13/2013
Posts: 112



A team of researchers from Japan found that Alzheimer’s symptoms can be reduced when sugars are averted from binding to one of the disease key enzymes, named BACE1. The study entitled “An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer’s disease“, was published in EMBO Molecular Medicine.

Alzheimer’s disease is caused by the formation of atypical Aβ plaques in the brain when the molecule APP is abnormally cut by the enzyme BACE1. Thus, developing treatments that block BACE1 from cleaving APP is becoming an area of increasing research in Alzheimer’s disease. However, it is necessary to perform this without affecting the vital processes that are controlled by normal BACE1 activity.

Yasuhiko Kizuka and colleagues from the RIKEN-Max Planck Joint Research Center determined that the binding of a specific sugar with an enzyme called GnT-III, modifies BACE1 in Alzheimer’s.

The researchers hypothesized that, by preventing this process they could reduce Alzheimer’s symptoms. To do this they crossed mice without GnT-III with other mice that express human APP in the brain. The results revealed that Aβ levels and plaque formation were reduced in these mice, and improvements in cognitive performance were observed.

Subsequently, the researchers demonstrated that removing the sugars of BACE1 is an effective method for inhibiting the plaque formation. By observing mice without GnT-II the researchers found lower levels of BACE1.

The researchers then tested this approach without disturbing other vital processes. The mice that were lacking GnT-III were healthy, and did not exhibit higher levels of other proteins that are cleaved by BACE1, showing that targeting GnT-III avoids BACE1 from cleaving APP, and can decrease Alzheimer’s symptoms possibly without adverse effects.

In a recent press release Kizuka commented concerning the results, “although a sugar change is often considered just a marker for disease or a specific cell type, our team has clearly demonstrated the functional role of a glycan during AD development. This work offers a good opportunity for many AD researchers to reconsider the importance of glycosylation.”

The results indicate that BACE1 is a factor that leads to the formation of Aβ plaques. Furthermore, the team of researchers verified that plaques are reduced and cognitive performance is improved when this action was prevented in mice through loss of the enzyme GnT-III. These findings add to the knowledge of the mechanisms of Alzheimer’s development thus potentially leading to the development of newer and better therapeutics. At the moment Kizuka and colleagues are searching for GnT-III inhibitors with a novel screening procedure using the RIKEN Program for Drug discovery and Medical Technology Platforms.



Lane Simonian
Posted: Tuesday, January 27, 2015 7:19 PM
Joined: 12/12/2011
Posts: 4845


This may be an important one as one BACE1 inhibitor has already been withdrawn due to liver damage. And BACE1 inhibitors may cause eye damage. If you can limit BACE1 from just cleaving the amyloid precursor protein that would be good.

In most people with Alzheimer's disease, BACE1 activation is an early step in the disease. The early steps are likely this: peroxynitrite formation--caspase-3 activation--BACE1 activation--c-terminal fragment of the amyloid precursor protein--g protein activation--peroxynitrtes.

http://www.ncbi.nlm.nih.gov/pubmed/11432978

But as most of the c-terminal fragments are converted into amyloid and as most g protein-coupled receptors are disabled by oxidation, this cycle is cut off in most people with Alzheimer's disease. My expectation is that BACE1 inhibitors would slow down the progression of the disease early on in most cases.

Serenoa
Posted: Wednesday, January 28, 2015 5:40 AM
Joined: 4/24/2012
Posts: 484


The molecule in question, the "aberrant sugar," that leads to the modification of BACE-1 is N-acetylglucosamine. It seems to have connections to glucose metabolism and hyperglycemia.

Hyperglycemia Inhibits eNOS activity...
http://www.jci.org/articles/view/11235/pdf


Lane Simonian
Posted: Wednesday, January 28, 2015 10:04 AM
Joined: 12/12/2011
Posts: 4845


Here is a similar study:

http://www.ncbi.nlm.nih.gov/pubmed/20125034

One way in which hyperglycemia inhibits Akt and endothelial nitric oxide synthase is via the eventual nitration of the insulin receptor substrate. This contributes to type 2 diabetes, cardiovascular dysfunction, and Alzheimer's disease.

http://www.sciencedirect.com/science/article/pii/S0925443913000689

http://www.ncbi.nlm.nih.gov/pubmed/11756341

Hyperglycemia also contributes to the reduction of endothelial nitric oxide by leading to the eventual oxidation of one of the co-factors for endothelial nitric oxide synthase (BH4). Superoxides are then produced instead (this aspect of biology was introduced to me by Tom(ek) several years ago on this site).

The effects of sugar on BACE1 activation and amyloid precursor processing appear to be direct, although sugar also works upstream to increase BACE1 activation.

Thanks, Serenoa for the post. There has just been a few of us posting here the last couple of weeks. It is always good to get your input and insights.