Presenilins and Alzheimer’s disease: the role of Aβ42

Summary

The presenilin proteins, localized predominantly to the endoplasmic reticulum, are multi-transmembrane spanning proteins that are processed to form an approximately 27kD N-terminal fragment and a corresponding 19kD C-terminal fragment. Mutations in the presenilin 1 and presenilin 2 genes have been identified that cause early onset familial Alzheimer’s disease Analysis of plasma and fibroblasts from patients revealed that these mutations increase the concentration of Aβ42 Cells and transgenic animals containing these mutations both give rise to increases in the extracellular concentration of this peptide providing further evidence for the role of Aβ, particularly Aβ42, in Alzheimer’s disease. These data provide strong evidence that alterations in Aβ concentration are an early and critical event in the pathology of Alzheimer’s disease.

Ever since the initial isolation of Aβ and the subsequent cloning of the precursor molecule, the role of Aβ in Alzheimer’s disease (AD) has been a topic of considerable interest and even more considerable controversy (Glenner and Wong, 1984; Kang et aI., 1987). Aβ is a highly amyloidogenic peptide that is invariably deposited in all forms of Alzheimer’s disease. The peptide is derived through the combined actions of β and y secretase activities from a series of 695-770 amino acid precursor proteins that are collectively referred to as the β amyloid protein precursor (βAPP)(Fig. 1).

To date, mutations in three distinct genes, on three separate chromosomes have been identified that cause AD (Eckman et aI., 1997; Levy-Lahad et aI., 1995; Mullan et aI., 1992; Sherrington et aI., 1995). These are the βAPP gene on chromosome 21, the presenilin 1 gene on chromosome 14, and the presenilin 2 gene on chromosome 1. In order to determine the role of Aβ, in particular Aβ42, in AD we have focused our efforts on examining the effects of these mutations on extracellular Aβ concentration in a wide range of model systems.

Prior to the identification of presenilin 1, and subsequently the presenilin 2 genes, we undertook a large collaborative effort to investigate alterations in extracellular Aβ concentration in fibroblast conditioned medium and in plasma obtained from chromosome 14 and chromosome 1 FAD-linked kindreds. In this series of experiments no significant alterations in the concentration of Aβ1-40 were detected either in plasma or in fibroblast conditioned medium from affected family members. A significant elevation in Aβ42, how ever, was observed providing evidence that like the βAPP mutations that we and others had previously examined, the presenilin mutations were causing alterations in the concentration of Aβ in ways that were likely to foster deposition (Cai et aI., 1993; Citron et aI., 1992; Eckman et aI., 1997; Scheuner et aI., 1996; Suzuki et aI., 1994; Younkin, 1995). Importantly, these elevations in Aβ concentration were observed in plasma obtained from pre-symptomatic carriers, decades before behavioral changes and, presumably, overt plaque deposition.

Following the identification of mutations in the presenilin 1 and presenilin 2 genes that cause AD, we undertook several collaborative efforts to examine the effect of over expression of these mutations in both transfected cells and transgenic animals (Borchelt et aI., 1996; Duff et aI., 1996). In these experiments, we continued to observe elevations in the concentration of Aβ42 both in conditioned medium from 293 cells and in brains of transgenic mice overexpressing FAD-linked presenilin mutations compared to control lines. Importantly, these studies demonstrated that the Aβ alterations observed in patients with these mutations could be extended into model systems and that these elevations occur in the brain prior to overt Aβ deposition in the form of plaques. Thus, these analyses have demonstrated that all of the early onset FAD-linked mutations that have thus far been analyzed increase the concentration of Aβ ending at Aβ42 (Fig. 2). This provides strong evidence that alterations in Aβ concentration are an early and critical event in the pathology of AD.

While these alterations in Aβ concentration represent an invariant feature in FAD-linked forms of Alzheimer’s disease, it should not be taken as proof that changes in Aβ concentration are the basis for the pathogenesis of the disease. It remains plausible, for example, that these changes are merely a tightly linked, early marker of disease. Until transgenic animals are produced which overexpress only Aβ and display behavioral pathology akin to AD, or drugs that specifically lower Aβ are found to be effective in staving off the progression of the disease in humans, the question of the true involvement of Aβ in the generation of AD will remain open.