Targeting amyloid precursor protein

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid plaques composed of the amyloid b peptide (Ab). According to the amyloid hypothesis, accumulation of Ab in the brain is the primary cause driving AD pathogenesis, and reducing Ab would ameliorate AD symptoms. Ab is derived by sequential proteolytic cleavage from the amyloid precursor protein (APP), a type I transmembrane protein with a large extracellular domain and a short cytoplasmic region. Cleavage by b-secretase releases a large soluble Nterminal APP ectodomain fragment (sAPPb), and subsequent action of c-secretase on the remaining membranebound portion of APP produces Ab. Alternatively, APP can be processed by a-secretase, which releases sAPPa and cleaves within the Ab sequence, thus precluding Ab formation by c-secretase processing (Fig. 1A). Whereas a-secretase activity is mainly localized to the cellular surface, b-secretase and c-secretase activity is predominantly found in endosomal compartments. Therefore, processing of APP into amyloidogenic (Ab) and nonamyloidogenic fragments is highly dependent on its intracellular itinerary. Consequently, altered subcellular targeting of APP directly affects the degree to which Ab is generated. Mutations in APP or in components of the c-secretase result in increased Ab production and cause the rare early onset familial form of AD. These genetic defects are usually not seen in the late onset form of AD (LOAD) that accounts for 95% of all cases. Numerous genetic studies have been undertaken to identify candidate genes underlying the complex genetics of LOAD. Among the identified genetic variations, those found in genes coding for proteins that may partake in the subcellular sorting of APP attract much attention. This attention is justified because mistargeting of APP has been found to cause amyloidogenic processing, and only a limited number of such genes have yet been identified. Previous studies established that inherited variants in the gene encoding the Vps10p-domain (Vps10p-D) receptor SorLA alter the risk for AD. SorLA (also termed LR11 or SORL1) directly interacts with APP and affects its intracellular transport and processing, and an inverse correlation between SorLA levels and Ab production in neurons has been observed. An association between another Vps10p-D receptor, SorCS1, and AD has been previously suggested by different genetic studies. Based on these findings, Reitz and colleagues analyzed a potential role of SorCS1 in AD, which is reported in this issue of Annals of Neurology. Their genetic association study of 16 single nucleotide polymorphisms (SNPs) in 6 independent data sets establishes SORCS1 as a LOAD gene. In accordance, expression analysis revealed lower SorCS1 levels in the amygdala from AD brains as compared to unaffected brains. Moreover, biochemical experiments suggest a direct interaction of SorCS1 and APP, and cellular analysis demonstrates that high SorCS1 expression levels result in a modest decrease of Ab, and a reduction of SorCS1 expression leads to an increase of Ab levels. Taken together, the observations by Reitz and colleagues strongly support the hypothesis that SorCS1 expression is associated with AD pathogenesis, presumably through altered secretase processing of APP. Their results are in accordance with another current publication demonstrating an interaction of SorCS1 and APP and showing that SorCS1 overexpression is a negative regulator of Ab levels. The present observations are reminiscent of SorLA function in AD. Both proteins are members of the Vps10p-D receptor family and regarded as putative sorting receptors. SorCS1 is expressed in at least 7 alternative isoforms with identical extracellular and transmembrane moieties, but different cytoplasmic domains which convey varying trafficking properties Whereas some cytoplasmic domains mediate rapid cellular uptake of ligands and target cargo to lysosomes, others direct the receptor to the cellular surface and do not mediate rapid internalization. However, none of the SorCS1 isoforms is engaged in Golgi-endosomal transport. This is an important difference from SorLA, which conveys this type of transport and acts as a retention factor for APP in Golgi compartments (see Fig. 1B). Therefore, it is likely that SorCS1 has a function different from SorLA in APP trafficking. Depending on the isoform involved, SorCS1 may stabilize APP at the cellular surface or may target APP to specific endosomal compartments (see Fig. 1C). However, most cellular observations were made in non-neuronal cells. In neurons, SorCS1 might serve additional specialized sorting functions. Further studies are needed, and the SorCS1 gene has to go through a