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HotSpots ‐ Cutting it close: new insights into presenilin‐1 function

The pathological hallmark of Alzheimer disease (AD) is the accumulation of a highly amyloidogenic 42-amino acid peptide (Ab42) in senile plaques as an early and invariant pathogenic event. This peptide is generated from the proteolytic cleavage of the b-amyloid precursor protein (APP) by sequential proteolytic cleavages by band then g-secretase (Fig. 2). Not surprisingly, there is tremendous interest in identifying these secretases and developing therapeutic agents based on redirecting APP processing towards a nonamyloidogenic pathway. Of the four genes known to be involved in inherited susceptibility to early-onset AD (presenilin-1, presenilin-2, apoplipoprotein E, and APP), presenilin-1 has attracted particular attention because the AD-associated mutations in presenilin-1 enhance g-secretase activity and result in increased production of the neurotoxic Ab42 peptide. Other evidence in transfected cells and in transgenic mice also suggests that presenilin-1 and g-secretase activity are functionally associated. A clue to the function of presenilin-1 was the discovery that presenilin-1 appears to be involved in the analogous proteolytic processing of Notch. Notch, like APP, is a large, single transmembrane cell surface protein that undergoes two sequential proteolytic processing events in the secretory compartment of cells. Notch is first cleaved extracellularly by furin to generate two fragments that form the functional receptor (Fig. 2). After binding the Notch ligand (Delta), Notch is further cleaved within the transmembrane domain by an unidentified protease analogous to g-secretase. Release of the Notch intracellular domain (NICD) by this second cleavage event permits the translocation of NICD to the nucleus, where it can modulate gene expression associated with cell fate decisions during development. Four new papers now extend the connections between presenilin-1, g-secretase, and Notch proteolytic cleavage. First, Wolfe et al. define two critical aspartate residues (D257 and D385) in the presenilin-1 transmembrane domains 6 and 7, respectively, that are critical for presenilin-1-mediated proteolytic cleavage of APP. Mutations of either of these aspartate residues to alanine re-