Potter R, Patterson BW, Elbert DL, Ovod V, Kasten T, Sigurdson W, Mawuenyega K, Blazey T, Goate A, Chott R, Yarasheski KE, Holtzman DM, Morris JC, Benzinger TL, Bateman RJ.
Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers.
Sci Transl Med. 2013 Jun 12;5(189):189ra77.
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Potter and colleagues demonstrate clearly, in vivo, two phenomena we, as a field, have suspected for 10-15 years: Presenilin mutations cause an increase in Aβ42 in the human CNS, and some compartment, presumably early deposits, start to extract Aβ42 from the interstitial fluid long before the disease is manifest, and even before amyloid imaging can visualize deposits. The detailed effects on APP metabolism should be interpreted with regard to the detailed description of these effects in vitro (see Chávez-Gutiérrez et al., 2012). Clearly, the SILK setup developed at Washington University offers a high-definition system for developing an understanding of the precise mechanisms by which drugs modulate APP/Aβ metabolism.
Chávez-Gutiérrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, Lismont S, Zhou L, Van Cleynenbreugel S, Esselmann H, Wiltfang J, Serneels L, Karran E, Gijsen H, Schymkowitz J, Rousseau F, Broersen K, De Strooper B.
The mechanism of γ-Secretase dysfunction in familial Alzheimer disease.
EMBO J. 2012 May 16;31(10):2261-74.
One of the remarkable aspects of this work, in our view, is the strong evidence it provides for how the fundamental physical characteristics of proteins in biological environments, such as their concentration, influence intricate biological events leading to the onset of disease. Findings of this type are particularly exciting, since they raise the possibility of applying methods established for the study of small-molecule reactions, such as chemical kinetics, to significantly more complex biological processes. We feel that elucidating the connections between physical characteristics and biological consequences in the context of pathological protein aggregation is absolutely crucial for understanding the basis for neurodegeneration. The study by Potter et al. represents a key advance in this direction.