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Family with Alzheimer's Disease may Carry Clues to Treatment

For release: Wednesday, June 17, 2009

In the brains of people with Alzheimer's disease (AD), a toxic protein fragment called beta-amyloid accumulates in clumps that leave a path of damaged brain tissue.  Although age is the most powerful risk factor for AD, a small fraction of people develop the disease because of genetic mutations that trigger beta-amyloid accumulation.  In a recent study published in Science*, researchers described a family with a mutation that causes beta-amyloid accumulation and AD in some individuals, but could protect against the disease in others.

This mutant beta-amyloid could serve as a template for small, artificial proteins designed to inhibit beta-amyloid accumulation and stave off AD in the roughly 400,000 people diagnosed with it each year.

The study was led by Fabrizio Tagliavini, M.D., of the Istituto Nazionale Neurologico Carlo Besta in Milan, Italy; Mario Salmona, Ph.D., of the Istituto di Ricerche Farmacologiche Mario Negri in Milan; and Efrat Levy, Ph.D., of New York University School of Medicine in Orangeburg, New York.  It was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).

The study began when an Italian man with early-onset dementia visited Dr. Tagliavini's clinic in Milan.  The man had begun to develop memory problems at age 36, and became completely dependent on caregivers by age 44.  The man's younger sister also reported mild memory problems consistent with the first stages of AD.  This unusually early, rapid course of the disease hinted at a genetic origin, the researchers say.  Most people with AD have a sporadic form of the disease that is caused by a combination of genetic and environmental factors, and emerges sometime after age 60.

The researchers tested the patients' DNA for mutations in the few genes that have been linked to early-onset AD, including three genes called APP, presenilin-1 and presenilin‑2.  In both patients, the APP gene turned out to harbor a mutation, A673V, whose effects are unlike any other AD-linked mutation known.

Until now, all of the known genetic forms of AD were autosomal dominant, meaning that a mutation in just one copy of the APP gene or the presenilins is sufficient to cause the disease.  (With the exception of genes on the Y chromosome, people normally have two copies of every gene.)  In this study, the new APP mutation followed an autosomal recessive pattern.  Each of the patients had the A673V mutation in both copies of the APP gene while several of their relatives, including an 88 year-old aunt, had the mutation in just one copy of the gene and remained disease free.

The APP gene encodes the amyloid precursor protein, which is the source of the beta-amyloid fragment.  Even in the healthy brain, this protein is sliced apart by enzymes to produce the beta-amyloid fragment, but in the brains of people with AD, beta-amyloid changes its shape to form large amyloid deposits in the brain.  The researchers found that the A673V mutation resides within the small piece of APP that becomes beta-amyloid, and that it has unusual effects on the formation of beta-amyloid clumps.

When the researchers made a synthetic version of the mutant beta-amyloid and let it incubate in a test tube, they found that it formed clumps – or aggregates – faster than normal beta-amyloid, the kind that accumulates in the brains of individuals with sporadic AD.  However, when the mutant beta-amyloid was combined with normal beta-amyloid, the mixture formed aggregates more slowly than normal beta-amyloid did by itself.  Finally, when the researchers exposed a neuronal cell line to the mutant beta-amyloid, normal beta-amyloid or a mixture, the mutant protein alone was most toxic to the cells and the mixture was least toxic.

Those findings show that when the mutant beta-amyloid encounters normal amyloid, it interferes with the formation of aggregates.  The findings raise the surprising possibility that while having two copies of the A673V mutation is clearly detrimental, having just one copy of it might protect against AD, perhaps even the sporadic version of the disease.  The researchers plan to test whether the A673V mutation can protect against AD in mice carrying the autosomal dominant mutations that are known to trigger the disease. 

The researchers say it might be possible to design small, therapeutic proteins that mimic the effects of beta-amyloid containing the A673V mutation.  The location of A673V within beta-amyloid might also have therapeutic implications, they say. It sits within the N-terminus, a region at one end of beta-amyloid that most experts did not consider important for the formation of aggregates.  The new study suggests that the beta-amyloid N-terminus could make an effective target not only for synthetic proteins, but for other kinds of drugs as well.

-By Daniel Stimson, Ph.D.

*Di Fede G et al.  "A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis." Science, March 13, 2009, Vol. 323, pp. 1473-1477.

Last Modified June 17, 2009