Presenilins, Processing of β-Amyloid Precursor Protein, and Notch Signaling

Given the evidence that presenilin is required for processing of Notch and APP at transmembrane sites, there are a number of possibilities for the function of presenilin. One is that presenilin is required for the proper trafficking of Notch and APP to their protease(s), which may reside in an intracellular compartment. Another is that presenilin is required for the proper biogenesis or trafficking of the γ-secretase. Another is that presenilin is an essential cofactor for γ-secretase, and yet another is that presenilin itself is γ-secretase. The current data cannot distinguish among these possible functions.Wolfe et al. 1999xWolfe, M.S, Xia, W, Ostaszewski, B.L, Diehl, T.S, Kimberly, W.T, and Selkoe, D.J. Nature. 1999; 398: 513–517Crossref | PubMed | Scopus (1410)See all ReferencesWolfe et al. 1999 favor the idea that presenilin is itself γ-secretase. They focus on two transmembrane aspartate residues conserved in all known presenilins. Expression in cultured cells of presenilin constructs in which either of these two residues is mutated results in loss of presenilin activity as assayed by production of Aβ, even though these cells express wild-type presenilin-1 endogenously. The authors therefore conclude that these constructs act as dominant-negative presenilins. While wild-type presenilins are cleaved at a site in the cytosolic loop, the authors find that the aspartate mutants are not cleaved in this manner; they take this result as circumstantial evidence that this cleavage is mediated by presenilin-1 itself. They also point out that γ-secretase has some characteristics of aspartyl proteases and speculate that the conserved aspartate residues may contribute to an active protease site in presenilin.Wolfe et al. further find that Aβ can be produced by in vitro translation of an APP-derived construct in the presence of microsomes derived from wild-type cells but not when the microsomes are prepared from presenilin-1 mutant cells. The authors argue that presenilin-1 is not required for trafficking of APP, as little or no vesicular trafficking is expected to occur in their in vitro microsomal preparations, and they suggest that presenilin is required in the same subcellular compartment in which γ-secretase resides. An alternative possibility is that presenilin is required for the proper production, processing, or localization of γ-secretase or an essential cofactor. Presenilin could also have multiple functions, including trafficking of APP, only one of which is required in microsomes. As Wolfe et al. point out, conclusive evidence that presenilin is γ-secretase will require a purified, reconstituted system, which may be technically difficult to accomplish. A somewhat more tractable, but less conclusive, approach would be to determine whether the newly identified γ-secretase inhibitors can bind directly to presenilin with the appropriate kinetics.Even should the presenilins not have a role in trafficking, endocytosis appears to have an important role in the processing of APP and in the function of Notch. Inhibitors of endocytosis partially block the processing of APP by γ-secretase in cultured cells. shibire, which encodes the Drosophila dynamin small GTPase and is required for endocytosis, appears to be required for activation of Notch upon ligand binding (Seugnet et al. 1997xSeugnet, L, Simpson, P, and Haenlin, M. Dev. Biol. 1997; 192: 585–598Crossref | PubMed | Scopus (199)See all ReferencesSeugnet et al. 1997). Trafficking of APP and Notch could regulate accessibility to their protease(s). Hence, determining the subcellular compartments for various processing events may contribute importantly to understanding the events in Notch signaling and Aβ production as well as their regulation.The normal function of the presenilins is still elusive, and many other questions remain to be answered. How do the mutations associated with AD affect presenilin function? What is the extent of overlap between the Notch and APP processing machineries? Other genes implicated in the Notch pathway might also have a role in APP processing. Are Notch and APP the only molecules that require presenilins for proteolysis? A careful analysis of the phenotypes of presenilin mutants may reveal defects not found in Notch mutants. By unraveling the connection between Notch and the presenilins, researchers may find answers to long-standing questions regarding both Notch signaling and the pathogenesis of Alzheimer’s disease.*To whom correspondence should be addressed (e-mail: ynjan@itsa.ucsf.edu).