Alzheimer's
...ns, Selkoe and colleagues first needed to link PS mutations and excessive amyloid deposits in Alzheimer's patients. They did so by analyzing brain tissues of patients who had died from early onset familial Alzheimer's caused by PS1 mutations.3 That paper showed humans with mutant PS1 have twice as much of a particularly invidious form of plaque called Aß42 plaques in their brains as the average person with Alzheimer's. They had the correlation, but they were still missing the mechanism. So the Massachusetts group teamed up with the Canadian researchers; Selkoe's scientists played the biochemical troubleshooters to Hyslop's gene hunters. Selkoe initiated the investigation with in vitro work. But because of the collaboration with St. George Hyslop and his University of Toronto colleague George Carlson, they quickly moved on to mice. Both in vitro and in vivo, the researchers observed the same phenomenon: "Mutant presenilins always increase significantly the production of this particularly obnoxious amyloid ß peptide, Aß42 by cells." That finding jelled with the earlier observation about excess Aß42 plaques in the PS1 gene carrier's brain. Several other papers in the same time frame reported similar findings.4,5,6 They all received attention because the problem represented a lightning rod in the Alzheimer's field. "It was very important to determine whether presenilins--an unequivocable cause of Alzheimer's disease--elevated Aß42 and thus worked through amyloids, because amyloid has been very controversial in the Alzheimer's field," Selkoe says. He suspects his paper received somewhat more citations than similar papers published about the same time because his groups' paper reported in vitro and in vivo results. The partnership with the Canadian lab, which initially reported the first PS1 mutation, was a real plus. "It was a very nice collaboration." Since then, Selkoe and colleagues have further refined their search for the mechanism of presenilins. They homed in on precisely how PS mutations lead to higher levels of Aß42 and consequently Alzheimer's. Mutating two aspartic acid residues located in the transmembrane regions of PS1 markedly reduces a cell's ability to produce Aß peptides.7 "When you knock out those aspartates, presenilin no longer functions properly," Selkoe explains. "It now makes far less Aß. Aß42 and the more common Aß40 fall to very low levels." Selkoe suspects that the more recent paper, taken together with this Hot Pa...