A genetic mutation in an Italian family causes an early-onset form of Alzheimer’s disease when it is inherited from both parents but apparently prevents the disease when it is inherited from only one. The finding, described in the March 13 issue of Science, adds a new twist to the Alzheimer’s mystery and may have practical applications.
The mutant gene’s apparent preventive effect “certainly opens up the possibility of therapies,” says Thomas Wisniewski, a neurologist and pathologist at New York University whose research has focused on the formation of amyloid deposits in Alzheimer’s.
Fabrizio Tagliavini and colleagues at the Carlo Besta National Neurological Institute in Milan found the mutated gene in an Italian man who had developed a progressive, Alzheimer’s-like dementia at age 36. The mutation, which they named “A673V,” results from the change of a single nucleotide, or genetic building-block, at codon position 673 of the gene that codes for amyloid precursor protein (APP).
In the past two decades, other mutations within the APP gene, or in genes that affect APP’s processing, have been linked to early-onset, familial forms of the disease. These links and related findings have encouraged many researchers to conclude that the brain-cell destruction of Alzheimer’s—even in its nonfamilial, late-onset form—is triggered when a subprotein of APP, beta-amyloid, somehow is produced in abnormally large amounts. Insoluble, clumped fibrils (fibers approximately 1nanometer in diameter) of beta-amyloid are detectable in the dead and dying brain tissue of people with Alzheimer’s, and these “amyloid plaques” have long been considered one of the major pathological markers of the disease.
However, all other APP mutations previously described in familial Alzheimer’s cases appear to be dominant mutations, which means that they cause disease if even a single copy is present in cells (a person’s genome contains two copies of most genes—one copy from each parent).
By contrast, Tagliavini and his group report that the A673V mutation is recessive, meaning that it causes disease only if present in both copies of the APP gene. The researchers found the mutation in both copies of the APP gene in the affected man and in a cognitively impaired younger sister. Other relatives who had inherited only a single copy of the A673V mutation appeared to be unaffected.
Several of these single-copy carriers “reached an advanced age without any sign of cognitive decline,” Tagliavini says, including one who was 88 years old at the time of the study. Tagliavini wondered how this could be, as even in the general population the prevalence of Alzheimer’s is very high at such an age. After studying the activity of the mutant APP and normal APP in cell cultures, the researchers concluded that the mixture of the two protected against the disease.
On its own, the mutant APP and its resulting mutant beta-amyloid aggregated into larger clumps, clumped more quickly and showed more toxicity to host cells, compared with normal APP and beta-amyloid. Yet when normal APP and mutant APP were present in the same cell culture system, their resulting beta-amyloid proteins interacted in a way that apparently inhibited the formation of insoluble clumps. The amyloid clumps that formed from this mix of mutant and normal APP were smaller than usual, took much longer to form, were much easier to dissolve and in preliminary tests also seemed less toxic to nearby cells.
The formation of amyloid plaques in the brain appears to occur at an early stage of the disease, perhaps a decade or more before clinical signs are evident [see news story “Targeting Amyloid in Alzheimer’s Disease: No Longer Enough?”]. Many researchers hope that preventing the buildup of plaques will prevent the progress of the disease. Some labs have tried to do this by developing compounds that inhibit amyloid proteins from misfolding and sticking together. As Wisniewski notes, small proteins, or peptides, whose sequences contain the A673V mutation might accomplish the same trick. Since reading the Tagliavini group’s paper, he says, “I’ve been playing around with different peptide sequences to see what might be useful.”
Tagliavini says that his lab, too, is developing peptides that contain the mutation and plans to test them in animal models of Alzheimer’s. His researchers have developed transgenic mice with single or double copies of the A673V mutation so they can further study the mutation’s effect on amyloid formation.