When Alzheimer's disease strikes, it is a particularly cruel blow.Family members can only watch as the once capable Alzheimer'ssufferer slowly loses memory and independence. Even crueler still,for some families, the disease strikes at age 40 or 50 rather than 70 or80. A mutation in one of three genes will cause Alzheimer's disease(AD) to take this accelerated course, but as yet scientists don't knowhow.

New results from researchers at the University of California, in SanDiego (UCSD), demonstrate that these three proteins interact and theby-product of that interaction may be the hallmark protein thataccumulates in the brains of AD patients.

"We know that these genes are intimately involved in AD," said S.Jonathan Singer, a professor at UCSD whose work is reported in theOct. 29 Proceedings of the National Academy of Sciences. "Now, weare beginning to see how they might be implicated."

AD is characterized by protein "plaques" accumulating in the brain.Beta-amyloid is the key protein in these plaques which manyinvestigators believe are in some way responsible for AD.

Lending credence to this notion, the first of the three genes associatedwith early-onset or familial Alzheimer's disease (FAD) was the beta-amyloid precursor protein (BAPP). However, only a small fraction ofall FAD cases are the result of mutations in BAPP. The rest are theresult of mutations in two recently discovered genes, S182 andSTM2. These two genes produce related proteins, but their normalfunctions are not known.

"These three genes account for all of the cases of FAD," saidNazneen Dewji, an assistant professor at the UCSD school ofmedicine and co-author of the paper. "So, it seems reasonable thatthey must somehow interact."

However, because the products of these genes are all membrane-bound proteins, it was not clear how they would interact. Singer andDewji proposed that cells containing either S182 or STM2 could anddid bind to those containing BAPP for normal neural functioning anddevelopment. To test this hypothesis, the researchers created cellswith either BAPP, S182 or STM2 in their cell membranes. BAPP andS182 cells would stick to each other to form clumps. BAPP andSTM2 cells did so as well. Excess BAPP in the cell media couldprevent the aggregates from forming.

Singer speculated that when these proteins stick to each other in thenormal brain, it triggers some sort of signal; but as an unfortunate by-product, it degrades BAPP into beta-amyloid which then accumulatesand eventually leads to AD. Mutations in one of these three proteinsmay simply accelerate the process.

"We have proven that these proteins can bind with each other onadjacent cells," Singer said. "It's a way of explaining how these tworecently discovered proteins could participate in the formation ofbeta-amyloid."

The researchers have yet to demonstrate that the interaction betweenthese three proteins actually cause beta-amyloid to build up in thebrain or even degrade beta-amyloid in the first place. Dewji toldBioWorld Today that these concerns are the next order of business.

"This genetic evidence is the linchpin that proves that beta-amyloidplays an important role in AD," Singer said. The challenge will bedefining that role. n

-- Lisa Seachrist Washington Editor

(c) 1997 American Health Consultants. All rights reserved.

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