Like glass, paper and aluminum, many cellular proteins are recycled. Amyloid precursor protein (APP) is an integral membrane protein in neurons. During recycling, APP is vulnerable to proteases that digest it into its neurotoxic form, A
;, which aggregates to produce the amyloid plaques associated with Alzheimer disease. Rogaeva et al. report that variants of a protein involved in APP recycling are associated with Alzheimer disease in a recent article in Nature Genetics.
APP is recycled through endosomes and transfered to the trans-Golgi network by the retromer complex. Brains from individuals with Alzheimer disease show reduced expression of several retromer complex proteins, including the sortilin-related receptor SORL1 and vacuolar protein sorting 35 (VPS35), relative to brains from healthy individuals. Therefore, the authors screened for mutations in retromer complex genes in people with Alzheimer disease.
The authors screened for single nucleotide polymorphisms (SNPs) in VPS35, VPS26A, sortilin (SORT1), and the sortilin-related receptors SORCS1, SORCS2, SORCS3 and SORL1 in 124 north European and 228 Caribbean Hispanic families with late-onset familial Alzheimer disease. Then the authors screened candidate SNPs in four additional ethnically restricted data sets of affected and control individuals. Six intronic SNPs in SORL1 associated with Alzheimer disease.
Haplotype analysis showed that groups of SNPs that localized to either the 5' or 3' end of SORL1 were associated with Alzheimer disease. At the 5' end, a CGC haplotype at SNPs 8, 9 and 10 associated with Alzheimer disease in the Carribean Hispanic, Israeli Arab and north European data sets. Conversely, the TAT haplotype associated with reduced risk of Alzheimer disease in these data sets. At the 3' end, CTT at SNPs 22-24 and TTC at SNPs 23-25 associated with Alzheimer disease in the European cohorts. In a database of African American siblings, ACT and ACC haplotypes at SNPs 23-25 associated with Alzheimer disease.
Most of the SNPs associated with Alzheimer disease were intronic. The authors proposed that SORL1 variant alleles would cause altered gene expression. Quantitative real-time PCR showed reduced expression of SORL1 in lymphoblasts of people with the Alzheimer disease-associated CTT haplotype at SNPs 22-24 relative to controls.
How would reduced SORL1 expression affect APP processing? SORL1 immunoprecipitated with APP, but not with its proteolytic products. Cells transfected with excess SORL1 showed reductions in A; relative to cells transfected with empty vectors. In contrast, short interfering RNA complementary to SORL1 or the retromer protein VPS26A increased A; relative to control.
The authors concluded that normally, APP is shuttled from the endocytic pathway to the trans-Golgi network by the retromer complex. However, reduced expression of SORL1 compromises the retromer complex, and APP enters late endosomes and lysosomes, where it is digested into toxic A;. These data suggest that Alzheimer disease and other late-onset neurological disorders may be ameliorated by repairing cellular systems important in protein processing and sorting.