The team used the SNP databases to track the SORL1 gene in the populations studied, but did not actually pinpoint the precise changes in the gene that contribute to disease. "Now we need to go back and look in the regions around the clusters of SNPs that we tracked and see if we can find additional genetic changes that are either unique or enriched in the individuals with Alzheimer's," said St George-Hyslop. "Then we'll have the actual genetic variations that lead to the disease."
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 indepen
Source:Howard Hughes Medical Institute