We invite you to participate in this “offline” Forum discussion with past ARF advisors Peter Davies of Albert Einstein College of Medicine in the Bronx, New York, and Bart De Strooper at K.U. Leuven, Belgium. The goal of this discussion is to explore the implications of two recent papers, which have been generously made available by their respective publishers.
Note:You do not need to log-in to participate. Simply submit your comments below and the ARF Editorial Team will review and post to the page.
Bentahir M, Nyabi O, Verhamme J, Tolia A, Horre K, Wiltfang J, Esselmann H, De Strooper B. Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006 Feb;96(3):732-42. Epub 2006 Jan 9. Full text. We thank the International Society for Neurochemistry and the Journal of Neurochemistry for access to this paper.
Samir Kumar-Singh, Jessie Theuns, Bianca Van Broeck, Daniel Pirici, Krist’l Vennekens, Ellen Corsmit, Marc Cruts, Bart Dermaut, Rong Wang, Christine Van Broeckhoven. Mean Age-of_Onset of Familial Alzheimer Disease Caused by Presenilin Mutations Correlates with Both Increased Aβ42 and Decreased Aβ40. Human Mutation, In press. View Uncorrected Text [.pdf].
Introduction by Gabrielle Strobel
If in your own mind you had Peter Davies pigeonholed as a tau researcher, think again. While Davies’ penchant for skepticism and doubt has established him as an occasional thorn in the side of a dominant amyloid hypothesis, his work on tau is not the only avenue that got him there.
Like many researchers today, Davies actively studies both major arms of Alzheimer disease pathology, and it is the amyloid side that drew his questioning gaze to the topic of the present discussion. Last month, researchers led by Bart de Strooper, at K.U. Leuven, Belgium, and colleagues in Germany, reported their analysis of how five different clinical presenilin 1 mutations and one presenilin 2 mutation affect the function of the gamma-secretase complex. These scientists were pursuing the question of whether the mutations lead to a toxic gain of function (i.e. more Aβ42 production), or perhaps also to a partial loss of function—an idea that may seem murky, unwieldy, and inconveniently counterintuitive but that has nonetheless been picking up some steam with recent studies.
First author Mostafa Bentahir and colleagues reported a mixed picture. All the examined mutations compromised the secretase’s ability to process APP at a recently discovered epsilon cleavage site, while APP cleavage at the gamma site varied from mutation to mutation. Some mutations led to more Aβ42 production but others led to a drop in Aβ40 production, and it was this latter finding, together with the loss of epsilon cleavage, that caught Davies’ eye. “Once in a blue moon, a paper comes out that really changes my thinking in an important way. That just happened,” Davies wrote to ARF.
Soon after, a second study fueled the issue further. First author Samir Kumar-Singh and colleagues, led by ARF advisor Christine Van Broeckhoven at the University of Antwerp, Belgium, developed a new method to measure FAD effects on γ-secretase. Their motivation partly was to develop a robust tool for predicting the clinical severity of a given FAD mutation in patients but, lo and behold, they similarly found that of nine FAD mutations examined, all consistently lowered Aβ40 levels whereas only some drove up Aβ42. Kumar-Singh et al. also found that loss of Ab40 correlated quite well with the age at which disease began.
All these changes add up to an alteration of the Aβ42/Aβ40 ratio, which is widely assumed to be a key factor in AD pathogenesis. Here are some questions to consider: Just how important is it which side tips the ratio? Is this mostly a fine point, because the ratio itself is what has the relevant biological consequences? Or would a selective decrease of Aβ40 indeed have fundamental implications for pathogenesis, for therapeutic strategies? How about a selective loss of epsilon cleavage? More broadly, should the field pursue APP processing products other than Aβ with more vigor? Is catalytic activity per se the main Achilles heel of γ-secretase, or could it be its assembly, or even the way its different substrates dock, and then access that catalytic site? Which of these changes brings on disease?
- Schmidt ML, Lee VM, Forman M, Chiu TS, Trojanowski JQ. Monoclonal antibodies to a 100-kd protein reveal abundant A beta-negative plaques throughout gray matter of Alzheimer's disease brains. Am J Pathol. 1997 Jul;151(1):69-80. PubMed.