Alzheimer's disease: NMR pinpoints genetic clue

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  • Published: Jan 15, 2014
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Alzheimer's disease: NMR pinpoints genetic clue

Genetic variants

Researchers have turned to solution NMR spectroscopy to help them ascertain the structure and dynamics of the transmembrane portion of the protein amyloid precursor protein, APP, of which there are two genetic variants linked to familial, or hereditary Alzheimer's disease.

Researchers have turned to solution NMR spectroscopy to help them characterise the structure and dynamics of the transmembrane portion of the protein amyloid precursor protein, APP and the effects of two genetic variants linked to familial, or hereditary Alzheimer's disease at atomic resolutions.

Chunyu Wang and Wen Chen, Eric Gamache, David Rosenman, Jian Xie and Maria Lopez of the Department of Biological Sciences and the Center for Biotechnology and Interdisciplinary Studies at Rensselaer Polytechnic Institute in Troy, NY, working with Yue-Ming Li of the Molecular Pharmacology and Chemistry Program at the Memorial Sloan-Kettering Cancer Center in New York, USA, have new evidence that explains the development of familial Alzheimer's disease (FAD). AD itself is commonly a disease of old age with an increased incidence among aging populations. However, the important genetic variants of this disease while affecting only a small proportion of total Alzheimer's disease cases might provide clues as to how the more widespread, sporadic form of the disease develops. Research might, of course, also offer hope of one day finding a way to slow progression or otherwise treat all forms of the disease.

Signature sign

Wang and his colleagues have homed in on two genetic mutations - V44M and V44A - which cause FAD. They have now demonstrated how these mutations lead to biochemical changes associated with the devastating problems in the brain that give rise to the well-known symptoms of the disease.

The team explains that one of the main characteristics of FAD is the accumulation of the amyloid beta 42 peptide (a short chain of amino acid residues) in unusually high concentrations within the brain. Amyloid beta is a common signature of the senile plaques (fibrils) present in AD in general. In the healthy brain, amyloid beta-42 and the related peptide, amyloid beta-40, are both present but in a concentration ratio of approximately 1 to 9. This ratio is much higher in the brain of a patient with FAD. While the two peptides are almost identical structurally, the former a 40-residue chain, the latter having 42 residues, the 42-peptide is highly toxic to brain cells and its presence at high concentration leads to gradual memory failure.

"The mutations that cause FAD lead to an increased ratio of amyloid beta-42 over amyloid beta-40," Wang explains. "That's the biochemistry, and that has been observed by many people. But the question we asked is: how? How do the mutations lead to this increased ratio?"

Is the first cut the deepest?

There are hundreds of known genetic mutations linked to FAD, but they are all related to the processing of a large protein, the amyloid precursor protein (APP), which begins as a partially embedded protein present in the membranes of brain cells. Enzymes that snip off pieces of this embedded membrane protein eventually release amyloid beta-40 or -42. Indeed, the release of snippets of the protein takes place in several steps carried out by a sequence of enzymes making distinct cuts to APP at different positions. These cuts are carried out by beta- and gamma-secretase. The exact location of the cut by gamma-secretase will dictate whether releases amyloid-beta-42 or -40 will be released. If the enzyme, gamma-secretase makes the first cut at amino acid residue 48 (threonine 48, T48), then subsequent enzyme cleavages result in the release of 42. However, if the initial cut is at residue leucine 49 (L49), amyloid beta-40 emerges as the product.

Now, Wang's team have for the first time used solution phase nuclear magnetic resonance (a combination of carbon-13 and nitrogen-15 NOESY NMR, with isotopic selection and filtering combined with selective isotopic labeling) spectroscopy to study the three-dimensional structure and dynamics of the transmembrane portion of APP affected by the two genetic mutations. They have found that the two possible mutations cause a critical change to the T48 amino acid residue making it more likely that gamma-secretase will make its cut at this position T48, to produce more amyloid beta-42 rather than -40.

"The basic idea is that - in the mutated versions - this site, T48, becomes more open, more accessible to gamma-secretase by weakening helical hydrogen bonds," Wang explains. "What we found is that the FAD mutation basically opens up the T-48 site, which makes it more likely for the enzyme to produce amyloid beta-42. This site in the precursor protein might be a target for drug discovery for slowing or preventing the accumulation of amyloid beta-42 in FAD. If an inhibitor drug can prevent enzyme cleavage at this point and force it to occur at the requisite amino acid that would release -40, then the ration of 42 to 40 in patients might be held to a lower level.

"Ultimately we want to understand the interaction between APPTM and gamma-secretase at the atomic level and the enzyme mechanism to help cure Alzheimer’s disease," Wang told SpectroscopyNOW.

Related Links

Nature Commun, 2014, online: "Familial Alzheimer’s mutations within APPTM increase Ab42 production by enhancing accessibility of e-cleavage site"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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