Alzheimer’s Disease and Biophysics

November is Alzheimer’s Disease Awareness Month in the US. An estimated 5.3 million Americans suffer from the disease, which is particularly prevalent among people age 65 and older. We recently spoke with BPS member Chuck Sanders, Vanderbilt University, Departments of Biochemistry and Medicine, Center for Structural Biology, about his research related to Alzheimer’s disease, which has also affected his own family.

sanders_charles_croppedWhat is the connection between your research and Alzheimer’s disease?

While not without controversy, the production of the amyloid-beta polypeptide is still generally thought to be central to the development of Alzheimer’s disease.  My lab studies the immediate precursor of amyloid-beta, the 99 residue transmembrane C-terminal domain of the amyloid precursor protein (C99).

Why is your research important to those concerned about Alzheimer’s disease?

Developing an understanding of the structure and molecular interactions of C99 may provide the basis for developing strategies to prevent its cleavage by gamma-secretase to generate amyloid-beta.  This would be expected to help prevent or even treat Alzheimer’s disease.

How did you get into this area of research and how long have you been working on it?

I am embarrassed to say so, but we originally chose C99 as a target for structural studies when we tried to express and purify over 20 disease-linked human membrane proteins small enough for NMR analysis.  C99 was chosen because it was one of the only proteins that could be well-expressed in E. coli.  I note that after we started studying C99 my father was diagnosed with Alzheimer’s disease, so this project has taken on a very personal quality to me.

Do you receive public funding for this work? If so, from what agency?

Yes, we are very grateful to NIGMS for an ongoing RO1 grant that supports this project.  We also appreciate it that we also have had some previous (see grant) support for it from the Alzheimer’s Association.  I should add that we also recently obtained a grant from the BrightFocus foundation to start a new Alzheimer’s project on the TREM2 protein, but that is a different story.

Have you had any surprise findings thus far? 

Four!   First, the structure of C99 is more complicated and interesting than we expected.  It has a kinked transmembrane helix with flanking amphipathic helices as both termini.  Secondly, it binds cholesterol to form a stoichiometric complex and does so with physiologically-relevant affinity.  Third, the cholesterol binding site is built around GXXXG sequence motifs, which usually are thought to be associated with membrane protein oligomerization.  Fourth, its structure is remarkably tolerant of even major changes in membrane lipid composition.

What is particularly interesting about the work from the perspective of other researchers?

alzheimers blog image

Binding of cholesterol to the kinked transmembrane domain of C99 with a conformational rearrangement of a surface-associated N-terminal helix and loop to optimize hydrogen bonding of the cholesterol head group in the membrane (here represent as a yellow slab). Not show in this picture is the disordered N-terminus or a long disordered loop that connect the end of the transmembrane domain to a surface-associated C-terminal helix (also not shown). Figure from Y. Song et al. (2013) Biochemistry 52, 5051-5054.

There are over 1500 papers on the relationship of cholesterol to Alzheimer’s disease (with elevated neuronal cholesterol being thought to be a pro-AD factor).  Finding that a central protein in the amyloidogenic pathway binds cholesterol avidly leads to a series of testable hypotheses regarding how cholesterol promotes Alzheimer’s

What is particularly interesting about the work from the perspective of the public?

One might imagine that our work and the work of others suggests that lowering dietary cholesterol might help to prevent Alzheimer’s disease.  It remains to be seen if this is the case—damage of blood vessels to the brain by cholesterol-linked microinfarctions does seem to contribute to the pathology of Alzheimer’s.  However, with respect to possibly impacting amyloid-beta production it must be pointed out that dietary cholesterol cannot cross the blood-brain-barrier (BBB).  All the cholesterol found in neurons is made in the brain.  One wonders if the long term use (possibly over many years) of cholesterol lowering drugs that are able to cross the BBB might not have some benefit in helping to prevent or delay the onset of Alzheimer’s disease by reducing amyloid-beta production.

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