A newly discovered gene mutation found to cause Alzheimer鈥檚 disease when inherited from both parents may give protection from the disease when only one copy is inherited. The discovery may lead to a new treatment for the neurodegenerative condition.
A 44-year-old man with two copies of a mutation in a gene called APP first showed signs of Alzheimer鈥檚 in his mid-thirties. Yet his relatives with a single copy of the mutation 鈥� including an 88-year-old aunt 鈥� seem to be protected from the disease, new research suggests.
Mimicking this single-copy condition with a drug could offer a new way of treating Alzheimer鈥檚, says , a neurologist at Carlo Besta National Neurological Institute in Milan.
Advertisement
Tagliavini鈥檚 team uncovered the mutation in a person who showed signs of early-onset Alzheimer鈥檚 but who lacked mutations in other genes associated with this inherited form of the disease.
Stark contrast
Only a small percentage of Alzheimer鈥檚 cases are linked to a single, inherited mutation, yet researchers have made great strides in understanding the more common late-onset form of the disease by studying these mutations.
The gene in question, APP, makes a protein called A-beta, which sticks together in the brain and blocks neurons from communicating with one another. Many researchers argue that such clumps underlie the symptoms of Alzheimer鈥檚, such as memory and speech difficulties.
Six of the patient鈥檚 relatives with one copy of this mutation show no sign of Alzheimer鈥檚 disease, while a younger sister with two copies has some cognitive problems, but not full-blown Alzheimer鈥檚, Tagliavini says. This stands in stark contrast to other mutations known to cause early-onset Alzheimer鈥檚, where a single copy is enough to cause the disease.
Clump resistant
In a bid to explain this difference, Tagliavini鈥檚 team analysed cells taken from the 44-year-old man. His cells developed far more A-beta clumps than cells extracted from people without normal APP.
When the team mixed normal and mutant forms of the protein, the mixture clumped far less often than mutant protein or normal protein alone. This could be why the patient鈥檚 relatives with one copy of the mutation seem able to stave off Alzheimer鈥檚, he says.
Recreating this situation with a synthetic protein could offer a new way of treating the disease in people with two copies of the APP mutation, Tugliavini says. Indeed, his team found that a mutant protein just six units long (proteins are usually much longer) is enough to keep the proteins from aggregating into clumps.
This kind of smaller protein has a better chance of travelling from blood vessels, across the blood-brain barrier and into the brain, but Tagliavini admits the potential therapy will need much more tinkering 鈥� not to mention testing. 鈥淲e are very far from this point, but we can work on this,鈥� he says.
New perspective
鈥淭here are other anti-aggregation therapies that are much further along,鈥� notes , an Alzheimer鈥檚 expert at Harvard Medical School in Boston, who was not involved in the study.
Tanzi founded a that is now testing one such therapy in patients, but Tanzi says the more Alzheimer鈥檚 drugs that are in development, the better.
Whatever happens, the newly discovered APP mutation will change how researchers think about the genetics of the disease, he says. All previously identified mutations causing inherited Alzheimer鈥檚 are dominant, meaning that only one copy of the mutation is enough to cause the disease.
鈥淚t鈥檚 pretty exciting from a genetic standpoint because it鈥檚 the first recessive mutation we鈥檝e seen in Alzheimer鈥檚 to date,鈥� Tanzi says.
Journal reference: (DOI: 10.1126/science.1168979)
