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Mutated presenilins and Alzheimer's disease: the culprit could be calcium signaling

The human presenilin-1 (PS1) and the highly homologous presenilin-2 (PS2) genes code for transmembrane proteins with unknown functions. When mutated, the presenilins are implicated in early-onset familial Alzheimer’s disease (FAD). The presenilin transcripts encode novel proteins that resemble integral transmembrane proteins of roughly 450 amino acids and at least seven transmembrane domains. The PS1 gene is located at 14q24.3 and the PS2 gene at 1q31-q42. The PS1 gene was identified by direct cDNA selection of yeast artificial chromosomes containing the candidate chromosomal region. Subsequently, the PS2 gene was found by its high sequence homology with PS1 and its location within the candidate region defined by linkage studies. The genomic organization of the two presenilin genes is very similar, and full-length PS1 and PS2 are both encoded by 10 exons, indicating that they diverged from a single ancestral gene. However, different alternative splicing patterns were observed for PS1 and PS2, suggesting that the two proteins might have distinct functions. To date, more than 30 different missense mutations were described for PS1, while only two such mutations were detected in PS2. Several studies have shown that both FAD-linked PS1 and PS2 variants altered the proteolytic processing of the amyloid precursor protein (APP), resulting in elevated production of amyloid beta (Abeta), a 40 or 42 amino acid peptide, whose extracellular accumulation in brain tissues remains the most reproducible pathological hallmark of Alzheimer’s disease. The brain accumulation of Abeta is believed to directly contribute to the increased vulnerability of brain neurons of Alzheimer’s patients to apoptosis induced by free radical-mediated stress and other insults. However, the exact mechanisms responsible for the altered processing of APP in individuals carrying presenilin mutations remain unclear. The new study by Leissring et al. (1999) points towards a likely explanation. It has been known from previous studies that PS1 mutations affect intracellular calcium ion levels. Calcium ions are central regulators of cellular events, from gene transcription to the cell cycle and apoptosis. It was not known if FAD-associated PS2 mutations similarly affect intracellular calcium signaling pathways. Using fluorescent calcium imaging techniques, the effects of wild-type PS2 and both the identified human PS2 mutations on intracellular calcium signaling were examined in Xenopus oocytes expressing the wild-type or the two mutated PS2 proteins known to occur in FAD. The study demonstrated that IP3 mediated calcium sig-