Alzheimer's Disease

D. Scheuner, C. Eckman, M. Jensen, X. Song, M. Citron, N. Suzuki, T.D. Bird, J. Hardy, M. Hutton, W. Kukull, E. Larson, E. Levy-Lahad, M. Viitanen, E. Peskind, P. Poorkaj, G. Schellenberg, R. Tanzi, W. Wasco, L. Lannfelt, D. Selkoe, S. Younkin, "Secreted amyloid beta-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. (Cited in more than 270 papers since publication) Comments by Steven G. Younkin, director of research and professor of pharmacology at the Mayo Clinic in Jacksonville, Fla. Amyloidß plaques have been showing up in lots of places. They appear to play a major role in Creutzfeld-Jacob's disease--the human analogue of the neurodegenerative mad cow disease--and they've been linked to Alzheimer's disease (AD). (See story, opposite page.) Steven G. Younkin In AD, the core of these extracellular brain lesions is made up of the 1-42 fragment of the amyloid ß -protein (A ß ), which is released from a wide variety of cells following proteolysis of its precursor, amyloid beta-protein precursor (APP). The peptide's apparent role in the pathogenicity of Alzheimer's caught the eye of the pharmaceutical world in 1992, when several groups discovered that only the fully soluble 1-40 fragment of the Aß is normally secreted from cells. The two amino acids tacked on to the normal fragment make the new peptide (1-42) insoluble, causing it to form the core of plaques. Not long after that observation, further results showed that mutations in APP caused more Aß fragment 42 to be released from fibroblast cells in vitro and in vivo, and the race to unravel the genetic causes and mechanisms of Alzheimer's disease was on. Researchers wondered, are mutations of APP alone in spawning dangerous levels of Aß fragment 1-42? Two other proteins, called presenilin 1 and presenilin 2, seemed perfect candidates to test the question. Mutations in both cause early-onset AD, and both are far more common than mutations in APP. This paper "tested the hypothesis that A ß is an important cause of Alzheimer's disease, by asking if [other] mutations that cause early-onset AD are influencing the extracellular concentration of Aß fragment 1-42 the same way that mutations in APP do. As it turned out, the presenilin proteins do," says Steven G. Younkin, director of research and a professor of pharmacology at the Mayo Clinic in Jacksonville, Fla., and a lead author of the study. Although early-onset Alzheimer's disease accounts for only about 1 percent to 5 percent of all cases, studies of identical twins suggest that about 60 percent of cases involve risk factors, says Younkin, adding that the typical case of AD is clinically and pathological identical to the disease course of early-onset AD. Given the similarities, the paper points to potential therapeutic avenues for both early-onset and "sporadic" disease. "If you know that increased secretion of A beta fragment 1-42 can cause AD, which is what this data indicates, then the idea of reducing its concentration to stop deposition (formation of plaques) becomes a very good therapeutic strategy," says Younkin. Compounds that inhibit formation of fragment 1-42 complexes or prevent its deposition to form plaques could be an effective treatment, as could inhibition of the protease that digests APP to form the fragment in the first place. The findings in this paper and others touched off a major effort to develop compounds that can do just that. Younkin recalls that in recent meetings several pharmaceutical companies have announced plans to enter Phase I clinical trials with protease inhibitors.

Alzheimer's Disease

The Scientist Staff

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