Alzheimer's Disease

Edited by: Paul Smaglik M. Citron, D. Westaway, W.M. Xia, G. Carlson, T. Diehl, G. Levesque, K. Johnson-Wood, M. Lee, P. Seubert, A. Davis, D. Kholodenko, R. Motter, R. Sherrington, B. Perry, H. Yao, R. Strome, I. Lieberburg, J. Rommens, S. Kim, D. Schenk, P. Fraser, P.S. Hyslop, D.J. Selkoe, "Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid ß protein in both transfected cells and transgenic mice, Nature Medicine, 3:67-72, January 1997. (Cited in more than 200 papers since publication). Comments by Dennis J. Selkoe, professor of neurology and neuroscience, Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital Neurobiologists studying Alzheimer's disease agree that plaque deposits in the brain serve as significant signposts on the disease progression pathway. However, opinions differ as to whether those plaques--largely composed of amyloid ß proteins--cause the disease or are merely an effect of it. Dennis J. Selkoe, firmly in the causal camp, thinks evidence supporting his stance continues to grow as the pathway becomes better mapped.1 "I have believed for more than a decade that Aß protein buildup was the key, central event that causes Alzheimer's. I still believe that. And this paper is probably cited so frequently because it goes quite a way toward supporting that." The evidence that prompted this research and helped confirm Selkoe's stance came in 1995, when Peter St. George-Hyslop and his colleagues at the University of Toronto identified and cloned the presenilin 1(PS1) gene.2 That paper established a clear link between the earliest and latest points in the disease--PS1 mutations and Alzheimer's-type dementia. After that paper, "no one could deny that mutant presenilins caused Alzheimer's," Selkoe recalls. "The only question was, 'How did they cause the disease? How did they do their dirty work?'" To answer those questions, 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 Paper, maps another gap in Alzheimer's pathogenesis. Researchers have long attached the name "gamma secretase" to the unknown enzyme that cleaves the amyloid precursor protein (APP) to generate the amyloid ß peptides. In this Hot Paper, Selkoe and colleagues noted that PS mutations consistently increase that cutting by gamma secretase. The more recent paper dramatically expands that gene product's role. "Presenilin appears to be an unusual aspartyl protease that cuts APP release Aß," Selkoe notes. "It appears to be the elusive enzyme called gamma secretase." Those collective findings provide more than a map to understanding Alzheimer's progression; they serve up a potential target for treatment. "I predict that if you can block the action of presenilin in cutting APP to make Aß42, that would treat Alzheimer's and could even prevent it." However, the pharmaceutical industry must screen and characterize thousands of compounds to find such a presenilin inhibitor. Testing such a compound--once one exists--should finally answer the debate about whether plaques cause the disease or are merely signposts. "The solution to the amyloid hypothesis will have to come in the clinic," Selkoe concludes. "We'll have to prove it in people." E. Russo, "Search continues for biochemical pathway that leads to onset of Alzheimer's disease," The Scientist, 12[19]:10, Sept. 28, 1998. R. Sherrington et al., "Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease," Nature, 375:754-60, 1995. C.A. Lemere et al., "The E280A presenilin 1 Alzheimer mutation produces increased Aß42 deposition and severe cerebellar pathology," Nature Medicine, 2:1146-50, 1996. D. Scheuner et al., "Secreted amyloid ß-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease," Nature Medicine,2: 864-70, 1996. D.R. Borchelt et al., "Familial Alzheimer's disease-linked presenilin 1 variants elevate Aß 1-42/1-40 ratio in vitro and in vivo," Neuron,17: 1005-13, 1996. T. Tomita et al., "The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid ß ending at the 42nd (or 43rd) residue," Proceedings of the National Academy of Science, 94:2025-30, 1997. M.S. Wolfe et al., "Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity," Nature, 398:513-7, April 8, 1999.

Alzheimer's Disease

The Scientist Staff

Interested in reading more?

Become a Member of