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Arizona State University Researchers Try Novel Approach to Alzheimer’s Prevention

Written by: | news@biospace.com | Dated: Thursday, August 15th, 2019

 

 

Researchers at Arizona State University areexperimenting with a compound that might prevent Alzheimer’s and other neurodegenerative diseases, such as Parkinson’s disease, and potentially Down syndrome.

One of the hallmarks of Alzheimer’s is the accumulation in the brain of two different types of proteins, beta-amyloid and tau. Amyloid clumps in the spaces between nerve tissue, while tangles of tau crowd the bodies of neurons. For the last several decades, the majority of Alzheimer’s research has focused on beta-amyloid and ways to prevent or clear it. However, they have all failed and the beta-amyloid theory of Alzheimer’s has largely been discounted.

The major turning point occurred in March 2019 when Biogen largely abandoned its aducanumab programs in Alzheimer’s. Aducanumab is an antibody that targets beta-amyloid. Scientists generally feel that although beta-amyloid is involved in the disease, it is not the primary driver. For example, many believe that neuroinflammation is a key component of the disease and beta-amyloid is something that makes the damage caused by inflammation worse.

Travis Dunckley, an ASU-Banner Neurodegenerative Disease Research Center researcher and Christopher Hulme, medical chemist at the Arizona Center for Drug Discovery, are working with a drug dubbed DYR219. This drug inhibits an early pathway that is believed to be vital in the formation of both amyloid plaques and tau tangles.

“If you can block that process early, you can delay the downstream aggregation and formation of the pathologies,” Dunckley stated.

The drug inhibits DYRK1, a neuroactive kinase. One problem is that DYRK1 is important in early embryonic development, involved in cell growth and proliferation, and the differentiation of cells into mature neurons and dendritic spines related to nerve impulse transmission. However, in the mature brain, DYRK1 seems to be involved in pathologies linked to Alzheimer’s, Lewy body dementia, and Parkinson’s disease. It is also a central aspect of Down syndrome. People with a disorder in DYRK1 often develop Alzheimer’s early, often in their 40s and 50s.

When the DYRK1 kinase interacts with the amyloid precursor protein (APP), it adds a phosphate group, called phosphorylation—it also does this to tau. This increased phosphorylation of APP is thought to increase the formation of amyloid plaques, while in tau it leads to neurofibrillary tangles.

“The reason I’m excited about this, especially in the face of a lot of the recent high- profile clinical trial failures, is that this is really a different approach to treating the disease,” Dunckley stated. “What we’re trying to do is restore the normal phosphorylation of APP and tau, so that you don’t get those downstream pathologies.”

In mice, inhibiting DYRK1 decreased amyloid plaques and improved cognition. Mice are not humans, however, and develop plaques and tangles quickly, before Alzheimer’s disease causes neurodegeneration and cell loss. In humans with Alzheimer’s, amyloid and tau typically appear with advanced neuron death at about the same time, meaning that many of the drugs used to clear the protein tangles, even when effective at doing so, were too late to do anything about the damage already done to the brain.

People with Down syndrome have a greater risk of Alzheimer’s. Down syndrome is marked by three copies of chromosome 21. The DYRK1 gene is localized on chromosome 21 in the Down syndrome critical region. Overexpression of DYRK1 seems to be significantly involved with the learning defects associated with Down syndrome.

 

 

BioSpace source:

https://www.biospace.com/article/yet-another-new-approach-to-preventing-alzheimer-s-disease

 

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