Certain mutations in the presenilin-1 gene cause the neurodegenerative disorder Alzheimer’s disease. These same mutations also cause increased secretion from neurons of Aβ4(1–42), one form of the neurotoxic amyloid-β peptide (Aβ), which is probably the main contributor to the extracellular senile plaques characteristic of the brains of Alzheimer’s patients. Presenilin-1 is clearly important in generating Aβ, but what exactly does it do?

Aβ is generated within neurons from a larger precursor, the amyloid precursor protein (APP), by a series of cleavage events. The cleavage enzymes have not been identified yet, but are known hypothetically as α-, β- and γ-secretase. Researchers have speculated that presenilin-1 might actually be the elusive γ-secretase, but a problem has been that presenilin-1 and APP seem to be found in different places within neurons. Annaert and colleagues (J. Cell Biol. 147, 277–294; 1999) have now taken steps to tackle this question.

Figure provided by W. Annaert.

First, the authors showed that the active form of presenilin-1 is, as thought, located mainly in the early compartments of the secretory pathway — the endoplasmic reticulum (ER), the ER–Golgi intermediate compartment, and the early Golgi itself. But it isn’t found in later compartments, as shown here — little overlap is seen between staining for presenilin-1 (red) and synaptobrevin-II (green), a marker of synaptic vesicles. (The nucleus is shown in blue.) Then, Annaert et al. showed that APP ‘stubs’, generated by the initial, α-/β-secretase-mediated cleavage, are found in the same compartments as presenilin-1. Finally, they made use of APP mutants that become stalled at different points in the secretory and internalization pathways. One APP mutant, for example, is trapped in the ER, and, in neurons that carry clinical mutations in presenilin-1, this mutant is processed to Aβ4(1–42) and secreted in higher quantities than the wild-type peptide.

Despite these results, it still isn’t certain whether presenilin-1 is indeed γ-secretase. On the one hand, rather than being γ-secretase itself, presenilin-1 might instead control trafficking of APP or γ-secretase, and Annaert et al.’s results are compatible with this idea. But now we know that presenilin-1 and APP are found in the same places, the argument that presenilin-1 and γ-secretase are one and the same is certainly strengthened.