Howard Hughes Medical Institute (HHMI) is reporting that a group from the University of Toronto has located what seems to be a new gene linked to the most common form of Alzheimer’s disease.
In an advance online publication in Nature Genetics on January 14, 2007, St George-Hyslop and colleagues connected the gene to the disease in six different groups of people, although they did not pinpoint the exact genetic mutations in SORL1 responsible for Alzheimer’s. In their studies, the researchers used databases that include genetic information about people with and without Alzheimer’s disease. More than 6,800 individuals–45.8 percent of them affected with the disease–were included in the analysis, which is considered a large data set in the field, said St George-Hyslop.
“We looked for variations of SORL1 in nine different groups of people and found those variations to be associated with an increased risk of Alzheimer’s in six of them,” St George-Hyslop said. “That implies that SORL1 is not the only cause of Alzheimer’s, but it’s one of several. Some people with the disease will have a SORL1-related cause, and some won’t…”
After linking SORL1 to late-onset Alzheimer’s, the team investigated the gene’s function. Using cell culture studies, they discovered that decreasing the amount of SORL1 increased cells’ production of amyloid-beta, a toxic fragment of another protein that destroys neurons. Production of amyloid-beta is the key event in the progression of Alzheimer’s disease.
Amyloid-beta is made when cells improperly break down a protein called amyloid precursor protein (APP). Previous research had revealed that APP is subjected to a sequence of cellular events that either properly recycles APP or shunts it into cellular structures called endosomes, where it is chopped into amyloid-beta. Researchers had identified several genes involved in this cellular sorting process. St George Hyslop and his team reasoned that inherited defects in some of these proteins might cause more APP to be shunted into endosomes, causing more amyloid-beta to be made, thereby increasing risk for Alzheimer’s. When the team investigated these genes, only SORL1 was associated with an increased risk of Alzheimer’s.
“What we have now are three independent sets of observations, all implicating the SORL1 gene in Alzheimer’s disease,” said St George-Hyslop. “We started with an observation from pathologists, showing reduced SORL1 protein levels in the brains of patients with Alzheimer’s. Then we have the observation by us and other groups that if you reduce SORL1 expression–in either cell cultures or mice–you get an increase in the production of amyloid-beta. Now we can add our new observation that variants of the SORL1 gene are associated with an increased risk of Alzheimer’s.”
Picture caption: The green arrows track re-entry of APP from the cell surface when SORL1 is present. The red arrows show that, when SORL1 is absent, more APP moves into domains such as the late endosome/lysosome, where the black arrows show how it is subsequently cut by two enzymes, beta-secretase (BACE1) and gamma-secretase (PS1 y-sec), generating the neurotoxic amyloid beta-peptide (A&946;).