Abstract
Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain-containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer's disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n=11 840 cases, 10 931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on γ-secretase processing of APP. Several SNPs in SORL1, SORCS1, SORCS2 and SORCS3 were associated with AD. In addition, four specific linkage disequilibrium blocks in SORCS1, SORCS2 and SORCS3 showed additive epistatic effects on the risk of AD (P⩽0.0006). SORCS3, but not SORCS2 or SORT1, showed reduced expression in AD compared with control brains, but knockdown of all the three genes using short hairpin RNAs in HEK293 cells caused a significant threefold increase in APP processing (from P<0.001 to P<0.05). These findings indicate that in addition to SORL1 and SORCS1, variants in other members of the VPS10 domain receptor family (that is, SORCS1, SORCS2, SORCS3) are associated with AD risk and alter APP processing. More importantly, the results indicate that variants within these genes have epistatic effects on AD risk.
Highlights
A central event in the pathogenesis of Alzheimer’s disease (AD) is the deposition of amyloid b (Ab) 1–40 and Ab1–42 peptides generated by proteolytic cleavage by b- and g-secretase from a larger membrane-bound protein, the amyloid precursor protein (APP).[1]
In line with previous reports,[2] most of the significant single nucleotide polymorphism (SNP) in SORCS1 and SORCS2 are located in intron 1, which is adjacent to the exons encoding the vacuolar protein sorting 10 (VPS10) domain
None of the genotyped SNPs in sortilin 1 (SORT1) were significantly associated with AD (Supplementary Table 2)
Summary
A central event in the pathogenesis of Alzheimer’s disease (AD) is the deposition of amyloid b (Ab) 1–40 and Ab1–42 peptides generated by proteolytic cleavage by b- and g-secretase from a larger membrane-bound protein, the amyloid precursor protein (APP).[1] APP and the secretases are integral transmembrane proteins dynamically sorted through the plasma membrane. Modulation of APP sorting through the membrane or altering APP cleavage by secretase enzymes could affect the regulation of Ab production or processing. Variants in two members of the vacuolar protein sorting 10 (VPS10) domain-containing receptor protein family, sortilinrelated receptor (SORL1) and sortilin-related VPS10 domaincontaining receptor 1 (SORCS1), are associated with lateonset AD presumably through effects on APP sorting and cleavage.[2,3,4] The VPS10 domain-containing receptor protein family contains five type I membrane homologs (SORL1, sortilin (SORT1), SorCS1, SorCS2 and SorCS3),[5,6,7,8,9] that are expressed in the central nervous system.
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