sorLA (sorting protein-related receptor) is a type-1 membrane protein of unknown function that is expressed in neurons. Its homology to sorting receptors that shuttle between the plasma membrane, endosomes, and the Golgi suggests a related function in neuronal trafficking processes. Because expression of sorLA is reduced in the brain of patients with Alzheimer's disease (AD), we tested involvement of this receptor in intracellular transport and processing of the amyloid precursor protein (APP) to the amyloid ␤-peptide (A␤), the principal component of senile plaques. We demonstrate that sorLA interacts with APP in vitro and in living cells and that both proteins colocalize in endosomal and Golgi compartments. Overexpression of sorLA in neurons causes redistribution of APP to the Golgi and decreased processing to A␤, whereas ablation of sorLA expression in knockout mice results in increased levels of A␤ in the brain similar to the situation in AD patients. Thus, sorLA acts as a sorting receptor that protects APP from processing into A␤ and thereby reduces the burden of amyloidogenic peptide formation. Consequently, reduced receptor expression in the human brain may increase A␤ production and plaque formation and promote spontaneous AD.endocytic receptors ͉ knockout mouse ͉ neurodegeneration ͉ Vps10p-domain receptors S orting protein-related receptor (sorLA), also known as LR11, is a 250-kDa type-1 membrane protein of unknown function that is expressed in neurons of the central and peripheral nervous system (1-4). The protein is a member of a family of neuronal receptors that share structural similarity with the vacuolar protein sorting 10 protein (Vps10p), a sorting protein in yeast that transports carboxypeptidase Y from the Golgi to the vacuole (5). Other family members include the proneurotrophin receptor sortilin (6) and the head activator-binding protein in hydra (7). Because sorLA interacts with the family of GGA (Golgi-localizing, ␥-adaptin ear homology domain, ARFinteracting) adaptors that shuttle between the Golgi and endosomes͞lysosomes, the receptor was proposed to act in intracellular protein trafficking (8). The relevance of such sorLAmediated protein transport in neurons is unclear at present. However, expression profiling has demonstrated reduction of sorLA expression in the brain of patients suffering from Alzheimer's disease (AD), suggesting a causal role for the receptor in the pathogenesis of this disease (9).Central to the pathogenesis of AD is the proteolytic processing of a neuronal membrane protein called the amyloid precursor protein (APP). APP follows a complex intracellular trafficking pathway that influences processing to either a soluble fragment sAPP␣ (nonamyloidogenic) or to sAPP␤ and the insoluble amyloid ␤-peptide (A␤), the principal component of senile plaques (10). The rate of A␤ production is considered the major risk factor for onset of AD (10). En route through the secretory pathway to the cell surface, most newly synthesized APP molecules are cleaved into sAPP␣ by ␣-secretase;...

sorLA is a sorting receptor for amyloid precursor protein (APP) genetically linked to Alzheimer's disease (AD). Retromer, an adaptor complex in the endosome-to-Golgi retrieval pathway, has been implicated in APP transport because retromer deficiency leads to aberrant APP sorting and processing and levels of retromer proteins are altered in AD. Here we report that sorLA and retromer functionally interact in neurons to control trafficking and amyloidogenic processing of APP. We have identified a sequence (FANSHY) in the cytoplasmic domain of sorLA that is recognized by the VPS26 subunit of the retromer complex. Accordingly, we characterized the interaction between the retromer complex and sorLA and determined the role of retromer on sorLA-dependent sorting and processing of APP. Mutations in the VPS26 binding site resulted in receptor redistribution to the endosomal network, similar to the situation seen in cells with VPS26 knockdown. The sorLA mutant retained APP-binding activity but, as opposed to the wild-type receptor, misdirected APP into a distinct non-Golgi compartment, resulting in increased amyloid processing. In conclusion, our data provide a molecular link between reduced retromer expression and increased amyloidogenesis as seen in patients with sporadic AD.

SorLA has been recognized as a novel sorting receptor that regulates trafficking and processing of the amyloid precursor protein (APP) and that represents a significant risk factor for sporadic Alzheimer disease. Here, we investigated the cellular mechanisms that control intracellular trafficking of sorLA and their relevance for APP processing. We demonstrate that sorLA acts as a retention factor for APP in trans-Golgi compartments/ trans-Golgi network, preventing release of the precursor into regular processing pathways. Proper localization and activity of sorLA are dependent on functional interaction with GGA and PACS-1, adaptor proteins involved in protein transport to and from the trans-Golgi network. Aberrant targeting of sorLA to the recycling compartment or the plasma membrane causes faulty APP trafficking and imbalance in non-amyloidogenic and amyloidogenic processing fates. Thus, our findings identified altered routing of sorLA as a major cellular mechanism contributing to abnormal APP processing and enhanced amyloid ␤-peptide formation.

SORLA/SORL1 is a unique neuronal sorting receptor for the amyloid precursor protein that has been causally implicated in both sporadic and autosomal dominant familial forms of Alzheimer's disease (AD). Brain concentrations of SORLA are inversely correlated with amyloid-β (Aβ) in mouse models and AD patients, suggesting that increasing expression of this receptor could be a therapeutic option for decreasing the amount of amyloidogenic products in affected individuals. We characterize a new mouse model in which SORLA is overexpressed, and show a decrease in Aβ concentrations in mouse brain. We trace the underlying molecular mechanism to the ability of this receptor to direct lysosomal targeting of nascent Aβ peptides. Aβ binds to the amino-terminal VPS10P domain of SORLA, and this binding is impaired by a familial AD mutation in SORL1. Thus, loss of SORLA's Aβ sorting function is a potential cause of AD in patients, and SORLA may be a new therapeutic target for AD drug development.

SorLA/LR11 is a sorting receptor that regulates the intracellular transport and processing of the amyloid precursor protein (APP) in neurons. SorLA/LR11-mediated binding results in sequestration of APP in the Golgi and in protection from processing into the amyloid-beta peptide (Abeta), the principal component of senile plaques in Alzheimer's disease (AD). To gain insight into the molecular mechanisms governing sorLA and APP interaction, we have dissected the respective protein interacting domains. Using a fluorescence resonance energy transfer (FRET) based assay of protein proximity, we identified binding sites in the extracellular regions of both proteins. Fine mapping by surface plasmon resonance analysis and analytical ultracentrifugation of recombinant APP and sorLA fragments further narrowed down the binding domains to the cluster of complement-type repeats in sorLA that forms a 1:1 stoichiometric complex with the carbohydrate-linked domain of APP. These data shed new light on the molecular determinants of neuronal APP trafficking and processing and on possible targets for intervention with senile plaque formation in patients with AD.

Sortilin-related receptor with A-type repeats (SORLA) is a sorting receptor that impairs processing of amyloid precursor protein (APP) to soluble (s) APP and to the amyloid ␤-peptide in cultured neurons and is poorly expressed in patients with Alzheimer disease (AD). Here, we evaluated the consequences of Sorla gene defects on brain anatomy and function using mouse models of receptor deficiency. In line with a protective role for SORLA in APP metabolism, lack of the receptor results in increased amyloidogenic processing of endogenous APP and in aggravated plaque deposition when introduced into PDAPP mice expressing mutant human APP. Surprisingly, increased levels of sAPP caused by receptor deficiency correlate with profound stimulation of neuronal ERK signaling and with enhanced neurogenesis, providing in vivo support for neurotrophic functions of sAPP. Our data document a role for SORLA not only in control of plaque burden but also in APP-dependent neuronal signaling and suggest a molecular explanation for increased neurogenesis observed in some AD patients.Sortilin-related receptor with A-type repeats (SORLA), 4 also known as LR11 or SORL1 is a sorting receptor that controls intracellular transport and processing of the amyloid precursor protein (APP) in cultured neurons (1-4). The receptor shuttles between Golgi, plasma membrane, and endosomes (5), and determines residence time of the precursor protein in the various intracellular compartments (3). Most importantly, the receptor promotes retention of APP in subcellular compartments less favorable for processing and thereby reduces the extent of proteolytic breakdown into both amyloidogenic and non-amyloidogenic products. Consistent with its protective role in APP catabolism, increasing SORLA expression in cells reduces conversion of APP to the amyloid ␤-peptide (A␤) and soluble (s) APP fragments, while low levels of receptor activity accelerate generation of these processing products (3,4,6).Recently, a possible role for SORLA as a risk factor for sporadic Alzheimer disease (AD) was supported by the association of inherited gene variants with the occurrence of this disease in several populations (7,8). These findings support earlier studies that reported low levels of Sorla gene expression in patients suffering from sporadic AD, but not in individuals with familial forms of the disease that are caused by defects in genes encoding APP or presenilin 1 and 2 (9, 10).A substantial amount of data correlate SORLA activity with APP processing and A␤ production rates in cell cultures. Still, the normal physiological role of SORLA-dependent regulation of APP processing in vivo and the pathophysiological consequences of insufficient receptor activity in the brain remain poorly understood.Here, we used alternative mouse models with targeted Sorla gene disruption to address the molecular and pathophysiological consequences of impaired SORLA activity for neuronal function and AD pathology in vivo. Our findings identified a distinct increase in A␤ production and amyloid pl...

The extent of proteolytic processing of the amyloid precursor protein (APP) into neurotoxic amyloid-b (Ab) peptides is central to the pathology of Alzheimer's disease (AD). Accordingly, modifiers that increase Ab production rates are risk factors in the sporadic form of AD. In a novel systems biology approach, we combined quantitative biochemical studies with mathematical modelling to establish a kinetic model of amyloidogenic processing, and to evaluate the influence by SORLA/SORL1, an inhibitor of APP processing and important genetic risk factor. Contrary to previous hypotheses, our studies demonstrate that secretases represent allosteric enzymes that require cooperativity by APP oligomerization for efficient processing. Cooperativity enables swift adaptive changes in secretase activity with even small alterations in APP concentration. We also show that SORLA prevents APP oligomerization both in cultured cells and in the brain in vivo, eliminating the preferred form of the substrate and causing secretases to switch to a less efficient non-allosteric mode of action. These data represent the first mathematical description of the contribution of genetic risk factors to AD substantiating the relevance of subtle changes in SORLA levels for amyloidogenic processing as proposed for patients carrying SORL1 risk alleles.

Summary HtrA proteases and chaperones exhibit important roles in periplasmic protein quality control and stress responses. The genetic inactivation of htrA has been described for many bacterial pathogens. However, in some cases such as the gastric pathogen H elicobacter pylori, HtrA is secreted where it cleaves the tumour‐suppressor E‐cadherin interfering with gastric disease development, but the generation of htrA mutants is still lacking. Here, we show that the htrA gene locus is highly conserved in worldwide strains. HtrA presence was confirmed in 992 H . pylori isolates in gastric biopsy material from infected patients. Differential RNA‐sequencing (dRNA‐seq) indicated that htrA is encoded in an operon with two subsequent genes, HP1020 and HP1021. Genetic mutagenesis and complementation studies revealed that HP1020 and HP1021, but not htrA, can be mutated. In addition, we demonstrate that suppression of HtrA proteolytic activity with a newly developed inhibitor is sufficient to effectively kill H . pylori, but not other bacteria. We show that H elicobacter  htrA is an essential bifunctional gene with crucial intracellular and extracellular functions. Thus, we describe here the first microbe in which htrA is an indispensable gene, a situation unique in the bacterial kingdom. HtrA can therefore be considered a promising new target for anti‐bacterial therapy.