Abstract
Alzheimer’s disease (AD) represents one of the most dramatic threats to healthy aging and devising effective treatments for this devastating condition remains a major challenge in biomedical research. Much has been learned about the molecular concepts that govern proteolytic processing of the amyloid precursor protein to amyloid-β peptides (Aβ), and how accelerated accumulation of neurotoxic Aβ peptides underlies neuronal cell death in rare familial but also common sporadic forms of this disease. Out of a plethora of proposed modulators of amyloidogenic processing, one protein emerged as a key factor in AD pathology, a neuronal sorting receptor termed SORLA. Independent approaches using human genetics, clinical pathology, or exploratory studies in animal models all converge on this receptor that is now considered a central player in AD-related processes by many. This review will provide a comprehensive overview of the evidence implicating SORLA-mediated protein sorting in neurodegenerative processes, and how receptor gene variants in the human population impair functional receptor expression in sporadic but possibly also in autosomal-dominant forms of AD.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Undoubtedly, Alzheimer’s disease (AD) represents one of the most dramatic threats to healthy aging in all societies and devising effective treatments for this devastating condition remains a major challenge in biomedical research. Much has been learned about the molecular concepts that govern proteolytic processing of the amyloid precursor protein (APP) to amyloid-β peptides (Aβ), and how accelerated accumulation of neurotoxic Aβ peptides causes neurodegeneration in rare familial but also common sporadic forms of AD (see “Box” for details). Targeting the accumulation of Aβ in the brain of patients holds great promise for success in the clinics. However, currently, this approach is limited to few targets, such as β- and γ-secretases, the enzymes that breakdown APP to Aβ [18, 21]. Thus, major efforts have been undertaken in recent years to identify additional players in Aβ metabolism and action, and to validate their relevance as therapeutic targets in treatment of AD.
Out of a plethora of proposed modulators of APP processing, one protein emerges as a promising candidate in AD pathology, a sorting receptor called sorting-related receptor with A-type repeats (SORLA) (also known as SORL1 or LR11). Independent approaches using human genetics, clinical pathology, or functional studies in animal models all converge on this receptor that is now considered an important factor in AD-related processes by many. This review provides a timely overview of the evidence implicating SORLA in AD. We describe the association of SORL1, the gene encoding SORLA, with the occurrence of sporadic but also autosomal-dominant forms of AD. We detail studies in cell and animal models that identified the molecular mechanism of SORLA as neuronal sorting receptor in control of amyloidogenic processes in the brain. We discuss the functional implications of sequence variations in SORL1 found in individuals with AD, and we review (pre)clinical data that explore the predictive value of SORLA levels in assessment of risk and outcome of AD, and that document the therapeutic benefit of strengthening receptor activity in treatment of AD-related conditions.
SORLA, a neuronal sorting receptor in APP processing
The first evidence implicating SORLA in AD came from a study by Scherzer and colleagues who performed global gene expression profiling to identify genes differentially expressed in lymphoblasts and in brain autopsies from AD patients compared to control subjects. This study identified a 2.5-fold decrease in brain SORLA levels in some sporadic cases of AD. Loss of protein expression was seen in cortex and hippocampus, but not in the cerebellum of affected individuals [83]. SORLA is a 250 kDa transmembrane protein that was identified prior in a quest for novel lipoprotein receptors expressed in the mammalian brain [42, 102]. Although SORLA showed some structural resemblance to lipoprotein receptors, a novel structural element not seen in any mammalian protein before was most noteworthy (Fig. 1). This so-called VPS10P domain is a 700 amino acid module in the extracellular domain of the receptor that folds into a ten-bladed β-propeller and that represents a binding site for peptide ligands [46, 70]. The VPS10P domain had been identified initially in the vacuolar protein sorting 10 protein (VPS10P), a sorting factor in yeast that directs target proteins from the Golgi to lysosomal compartments [58]. Today, this domain is the unifying structural motif of a group of five related VPS10P domain receptors that act in intracellular sorting processes in neuronal and multiple non-neuronal cell types in the mammalian organism (reviewed in [101]) (Fig. 1).
Abundant expression of SORLA was seen in neurons throughout the central nervous system including cortex, hippocampus, cerebellum, and spinal cord [42, 102]. In neurons, SORLA mainly localized to intracellular compartments in the cell soma, suggesting a role for this receptor in vesicular protein transport [63]. Based on this assumption, two subsequent studies proposed a molecular concept whereby SORLA acts as a sorting factor for APP, guiding intracellular trafficking and processing of this precursor protein [4, 68]. In these studies, overexpression of SORLA in cell lines reduced [4, 68] while loss of expression in gene-targeted mice increased Aβ production [4], providing an explanatory model for why reduced SORL1 expression in some individuals with sporadic AD may promote neurodegeneration.
SORL1 is genetically implicated in late- and early onset forms of AD
Initial data on the role of SORLA in AD were met with considerable skepticism as SORLA appeared as one of many proposed modulators of APP processing. However, strong support for a causal involvement of this receptor in neurodegenerative disease came with genetic studies associating SORL1 gene variants with the occurrence of sporadic AD. In a pioneering study, Rogaeva et al. used a candidate gene approach to document association of inherited variants in SORL1 with sporadic AD in Caucasians [76]. This finding was replicated in some association studies, while others failed to confirm it (summarized in [74]). This controversy was attributed to allelic heterogeneity in various ethnicities and to the lack of statistical power due to small cohort sizes. Ultimately, this discrepancy was resolved by combining the findings of many studies in meta-analyses substantiating the association of SORL1 variants with sporadic AD [44, 74, 97]. Recently, genome-wide association studies (GWAS) confirmed association of SORL1 with the sporadic late-onset form of AD in populations of Caucasian and Asian origin [51, 62].
Taken together, a number of single nucleotide polymorphisms (SNPs) in SORL1 have been associated with the occurrence of sporadic AD. These SNPs include coding as well as non-coding sequence variations and cluster in two haplotype blocks in the 5′ and 3′ regions of the gene on human chromosome 11q23-q24 (see Fig. 2 for numbering of the SNPs). Refined clinical analyses document association of individual SNPs with distinct neuropathological features including deposition of senile plaques (SNP#8) and fibrillary tangles (SNP#10, rs11218343) [9, 25], and with loss of gray matter volume (SNP#23) [39] and hippocampal atrophy (SNP#21-26) [20]. SNPs in the 3′ haplotype block are associated with pathological alterations of AD biomarkers in cerebrospinal fluid (CSF), such as Aβ and tau [2, 24, 31, 47, 55], whereas SNP#8 [6], SNP#19 [75], and rs11218343 [64] predict longitudinal cognitive change. Interestingly, SNP#19 appears to have a gender bias impacting cognitive decline stronger in females than in males [75].
An exciting twist in the genetic of SORL1 came with the observation that sequence variations in this gene are also found in individuals suffering from autosomal-dominant forms of AD, rendering SORLA a potential culprit in both late- and early onset types of this disease [65, 69, 95]. So far, mutations in three genes have been shown to cause the rare early onset form of AD, namely APP, PSEN1 and PSEN2. However, the majority of individuals suffering from early onset AD lack obvious mutations in APP, PSEN1, and PSEN2, indicating the existence of additional genes that cause this aggressive form of neurodegeneration [30]. Using whole exome sequencing or candidate gene approaches, coding sequence variations in SORL1 have been identified in early onset cases of AD in which inheritance was consistent with autosomal-dominant transmission. Identified sequence variants in SORL1 include nonsense and frame shift as well as potentially damaging missense alterations [65, 69, 95]. Many of these coding variants were not seen in control subjects as exemplified in the study by Nicolas and colleagues [65] that identified a total of 50 rare missense variants (minor allele frequency <1 %), with 37 variants in AD cases but only 17 in control subjects. These data reached exome-wide significance when the analysis was restricted to a subset of patients with a positive family history. These observations still need to be interpreted with some caution as documentation of cosegregation of these variants in affected relatives has so far only been shown for two cases, p.G511R [69] and p.Y1816C [95]. However, if substantiated in further studies, these findings suggest SORL1 as a novel disease gene in autosomal-dominant forms of AD, lending further support to the central role of amyloidogenic processing in the etiology of this disorder.
SORLA, an inhibitor of amyloid-β peptide accumulation in the brain
What is the mechanism whereby SORLA acts as a risk factor in AD? This question has initially been addressed in cell lines (summarized in [100]), and recently also substantiated in transgenic mouse models, identifying SORLA’s mode of action as a neuronal sorting receptor for APP and Aβ. The basis for its action is the complex trafficking path whereby APP moves between intracellular compartments and the cell surface, determining the extent of Aβ accumulation (reviewed in [81]). In a simplified scheme (Fig. 3a), newly synthesized APP molecules traffic through the secretory pathway to the cell surface. In route, they encounter α-secretase, resulting in non-amyloidogenic cleavage (see also “Box”). Precursor molecules escaping non-amyloidogenic processing are internalized from the cell surface into endosomes. In endocytic compartments, APP is processed by β- and γ-secretases producing Aβ [28, 32, 72, 82]. Intracellular accumulation [8] as well as secretion of Aβ peptides, involving exosomes [71] and other means of exocytosis [7], contributes to the amyloidogenic burden in the brain. As it turns out, SORLA impairs amyloidogenic processes in two ways, both of which involve its ability to shuttle target proteins between secretory and endocytic compartments of the cell [41, 66, 85]. In one mechanism, SORLA acts as a sorting factor for APP retrogradely moving internalized precursors from early endosomes back to the trans-Golgi network (TGN) and slowing down exit from the Golgi, thereby reducing the number of APP molecules subjected to amyloidogenic processing (Fig. 3b). Consequently, overexpression of SORLA in neuronal and non-neuronal cell lines blocks APP processing and reduces Aβ production [4, 68, 76], while loss of SORLA increases Aβ levels and senile plaque burden in several mouse models of AD [4, 22, 77]. The second mode of receptor action involves the anterograde sorting of SORLA from the TGN to endosomes. This pathway not only serves to replenish receptor levels in endosomal compartments for APP retrieval, but it also results in lysosomal targeting of Aβ molecules that have been identified as another receptor ligand (Fig. 3b) [13].
Jointly, retrograde sorting of APP to the TGN and anterograde movement of Aβ to lysosomes reduce brain levels of Aβ and contribute to the protective action of SORLA in the brain. Its pathological relevance has been confirmed in unbiased siRNA screens that also identified this receptor as a major determining factor of Aβ levels in cells [15]. The quantitative contribution of either activity to the overall protective function of SORLA is difficult to assess. Based on mathematic models, the kinetic of SORLA and APP interaction appears as a major determinant of Aβ levels, arguing for a predominant role of the APP sorting pathway in defining the risk of AD [1, 53, 84]. In the healthy brain cortex, SORLA and APP are expressed in almost equimolar ratio, suggesting near complete saturation of APP molecules with sorting receptors [84]. Thus, reduced levels of SORLA, as in some individuals with sporadic AD, likely act through loss of protection of APP from processing.
Molecular and structural basis of SORLA action
Two protein modules in SORLA define its function as a neuronal sorting receptor in AD, namely binding sites for APP and Aβ in the extracellular region as well as recognition motifs for cytosolic adaptors in the receptor tail that govern intracellular trafficking. Cell and structural biology approaches have provided an in-depth view of the structural basis of these domains for receptor function.
The binding site for APP in SORLA has been mapped to the cluster of eleven complement-type repeats in the extracellular domain of the receptor that forms a 1:1 stoichiometric complex with a region in the extracellular domain of APP referred to as the carbohydrate-linked domain [4, 5]. Deleting this cluster of complement-type repeats abolishes the ability of SORLA to protect APP from processing [61]. A second site of interaction may involve the cytosolic domains of both proteins as shown by fluorescence life-time imaging microscopy [90] and by mutagenesis of the APP tail [50]. The interaction of SORLA and APP is blocked by signaling through β-adrenergic receptors via a yet unknown mechanism, resulting in impaired Golgi retrieval and in increased endosomal accumulation of APP [16]. The binding site for Aβ in SORLA has been mapped to the VPS10P domain using X-ray crystallography [46]. Disruption of this binding site reduces lysosomal catabolism of Aβ without impacting APP processing rates, suggesting that sorting of Aβ and APP is two distinct receptor functions [13]. The complement-type repeats are a feature of SORLA not shared by other VPS10P domain receptors (see Fig. 2). Also, Aβ binds to the VSP10P domain of SORLA but not to the closely related domain in sortilin [13], arguing for a unique role of SORLA among the members of the VPS10P domain gene family in control of amyloidogenic processing.
The second structural element with a decisive role in SORLA activity is the cytoplasmic tail of the receptor. This 54 amino acid domain harbors multiple motifs for protein–protein interaction and for post-translational modification (Fig. 4). Specifically, the tail includes binding sites for three cargo adaptor complexes, termed PACS1, GGA, and retromer that mediate the shuttling of SORLA between TGN and endosomes. Phosphofurin acidic cluster sorting protein 1 (PACS1) interacts with an acidic motif D2190DLGEDDED to mediate retrograde Golgi-to-endosome transport of the receptor [11, 85]. Retrograde sorting of SORLA is also governed by the retromer complex through binding of its VPS26 subunit to the motif F2172ANSHY in the receptor tail [26, 86, 87]. In contrast, anterograde sorting of SORLA is guided by the clathrin adaptors GGA1 and GGA2 (Golgi-localizing, γ-adaptin ear homology domain, ARF-interacting proteins) that bind to the D2207DVPMVIA element in the SORLA tail [36, 43, 85]. Adaptor protein (AP) 1 and 2 are tetrameric adaptor complexes that link cargo to the clathrin coat of endosomal and TGN vesicles. They also interact with the acidic motif in SORLA and possibly regulate endocytosis (AP2) and retrograde receptor sorting (AP1) [66]. Adaptor interactions are crucial for SORLA-dependent sorting and processing of APP, as deletion of individual adaptor-binding sites in the tail of SORLA causes the inability of the receptor to sort properly and results in aberrant routing and enhanced processing of APP in cells [11, 26, 36, 66, 85]. These distinct roles of anterograde versus retrograde sorting of SORLA have recently also been substantiated in vivo. Expression of mutant SORLA variants lacking the binding sites for retromer [23] or PACS1 [11] results in impaired retrograde routing of SORLA, and causes increased amyloidogenic processing of APP in the brain of transgenic mice. In contrast, in vivo disruption of the binding site for GGA blocks anterograde receptor sorting and reduces lysosomal catabolism of Aβ (and of SORLA) without impacting APP processing [23].
As well as directing receptor sorting, interactions at the tail of SORLA may also control receptor activities through signal transduction pathways, although the underlying concepts are not fully understood. Thus, binding of several kinases, including Ste-20-related proline-alanine-rich kinase (SPAK) [73], protein kinase C, as well as Rho-associated coiled-coil containing protein kinase (ROCK) 2 [37, 52] to the receptor tail has been documented. Phosphorylation of the cytoplasmic domain of SORLA at serine 2206 (possibly by ROCK2; Fig. 4) increases receptor activity and reduces APP processing [37].
Functional implications of SORL1 gene variants in AD
Having defined the molecular basis of SORLA action, one can now start to appreciate how rare SORL1 variants in the human population may influence the risk of sporadic or autosomal-dominant forms of AD. Obviously, many identified SNPs may not represent true functional variants, but be in linkage disequilibrium with yet unidentified sequence alterations. Still, the causal role of several SNPs in impacting SORLA expression and activity has been confirmed as detailed in the following.
Conceptually, non-coding SNPs may work through a change in SORL1 transcription (Fig. 2). Little is known about the mechanisms that control expression of SORL1 in cells, such as neurons. Typically, expression of SORL1 is higher in proliferative cell types and decreases upon cellular differentiation as shown for neuroblastoma cells [38]. SORL1 expression is controlled by DNA methylation [104] and by an enhancer element in exon 17 of the gene [10]. Several factors induce receptor expression, including hypoxia-inducible factor 1α [67], the omega-3 fatty acid DHA [57], and brain-derived neurotrophic factor (BDNF) [79]. Interestingly, neuronal expression of SORL1 may not only be controlled at the level of gene transcription but also by alternative splicing. Full-length but also SORL1 transcripts lacking exons 2 or 19 are found in the human brain. Levels of the transcript encoding the full-length receptor, but not those of the exon 2 deletion, are reduced in individuals with sporadic AD [29]. A long non-coding RNA that maps in an antisense direction to exon 1 in SORL1 induces alternative splicing and reduces expression of the full-length receptor. Expression of this non-coding RNA is up-regulated in the AD brain and coincides with increased Aβ formation in cells [17].
Consistent with a suspected impact of some risk SNPs on SORL1 transcription, Rogaeva and colleagues identified SNP#22-24 in the 3′ haplotype block (Fig. 2) to be associated with a 50 % reduction in mRNA levels in lymphoblasts of sporadic AD patients. Others showed association of SORL1 mRNA levels with rs661057 in the 5′ gene region [29] or with the 5′ haplotype block in a cohort of healthy controls [59]. Sequence variations encoded by the 5′ haplotype block (SNPs #8-10; Fig. 2) result in loss of inducibility of SORL1 by BDNF [103], while SNP#21 may impact splicing as predicted by in silico analysis [48]. Even some coding variants in SORL1 may act by altering SORLA expression. For example, four coding sequence variants found in cases of early onset AD (p.D54 fs, p.G447 fs, p.W1216X, p.C1478X) are proposed to reduce transcript levels through nonsense-mediated RNA decay [65, 95]. A silent mutation encoded by SNP #19 (p.S1187=) reduces the efficiency of SORLA translation by changing from frequent to rare codon usage in the disease-associated minor allele [12]. Collectively, different mechanisms have been suggested to underlie the observed association of SORL1 risk alleles with the production of functional transcripts. Why reduced expression of the receptor in some instances may cause late-onset, but in other cases early onset of AD remains a puzzling question that warrants further investigation.
Perhaps even more informative may be coding variants in SORL1 that abrogate distinct receptor functions as they may help in further elucidating the molecular architecture of the receptor polypeptide (Fig. 5). Mutation p.G511R was identified in two affected individuals from a pedigree consistent with an autosomal-dominant mode of inheritance of AD [69]. This mutation disrupts the binding site for Aβ in the VPS10P domain of SORLA, resulting in the inability of the mutant receptor to facilitate lysosomal catabolism of Aβ [13]. Three additional coding variants found in cases of sporadic AD map to the VPS10P domain (p.E270K, p.A528T) or to the β-propeller (p.T947M; Fig. 5). All three receptor variants coincide with impaired retrograde sorting of APP and enhanced Aβ production when expressed in cells [93]. Additional SORLA coding sequence variants in early onset AD cases target the cluster of complement-type repeats, the fibronectin-type 3 domains, or the retromer recognition motif in the cytoplasmic receptor tail [65, 95]. Although no functional data are available as yet, these sequence alterations may disrupt APP or adaptor interaction with SORLA.
SORLA, a target for diagnosis or treatment of AD?
SORLA is subject to proteolysis by metalloproteases, such as tumor necrosis factor-converting enzyme, resulting in shedding of the soluble ectodomain of the receptor [33, 35]. This soluble ectodomain can be detected in plasma and CSF. Ectodomain shedding disrupts the ability of SORLA to act as an intracellular sorting receptor but may serve to produce a soluble receptor fragment, termed soluble (s)SORLA, that acts as a signaling molecule. Such a function for sSORLA has recently been documented in bone morphogenetic protein signaling in adipose tissue [98]. While the relevance of sSORLA for AD-related processes still awaits clarification, the circulating levels of this fragment may provide an estimate of full-length receptor level or activity in brain tissue. Accordingly, several studies aimed at correlating sSORLA levels in CSF with brain pathology or with established biomarkers of AD, yet the results have been inconsistent so far. In some cohorts, the levels of sSORLA were significantly reduced in the lumbar samples of patients with mild to moderate probable AD as well as in ventricular CSF from autopsy-confirmed AD cases [56]. This observation would be in line with low levels of full-length SORLA being risk bearing. In contrast, others reported increased sSORLA levels in AD cases [40] or a positive association of sSORLA with BACE-1 activity [92] or sAPPβ and tau levels [3] in CSF of AD patients. As for these latter cases, a positive correlation of sSORLA levels with AD biomarkers may argue for enhanced ectodomain shedding as a pathological mechanism reducing the levels of active full-length receptor in the brain parenchyma.
While additional studies are warranted to substantiate sSORLA as a biomarker of AD, the therapeutic benefit of raising receptor levels to reduce the amyloidogenic burden is undisputed. As a proof of concept, increasing SORLA levels in the brain of transgenic mouse models has been shown to reduce Aβ levels, a mechanism attributed to the enhanced shunt of newly produced Aβ peptides into lysosomal catabolism in neurons [13]. Also, increasing brain SORLA levels by intracranial injection of BDNF has proven successful in reducing Aβ levels in mice [79]. An alternative strategy to strengthening the SORLA pathway may be provided by small molecules that stabilize the retromer complex. In cells, these molecular chaperones promote retrograde sorting of APP and decrease amyloidogenic processing, a mechanism that possibly works in a SORLA-dependent manner [60].
Outlook
This review has focused on a role of SORLA in sorting of APP and Aβ to provide working models for a protective function of this receptor in AD. However, undoubtedly, this receptor is not specific to sorting of APP and Aβ, but has other protein targets as well. Of particular relevance to neurodegenerative processes, SORLA is able to sort several neurotrophin receptors, including the BDNF receptor TrkB [78], the receptor for glial cell-line-derived neurotrophic factor called GFRα1 [27], and the ciliary neurotrophic factor receptor α [54]. Thus, SORLA may represent a disease gene on which pathways in amyloidogenic processing and in trophic support of neurons converge. Obviously, further investigations are required to explore this intriguing concept, but they certainly offer the potential for exciting new insights into the genetic basis and pathological mechanisms of neurodegenerative disease.
References
Alcantara JH, Lao AR, Ruivivar LA (2016) Stability analysis of the ODE model representation of amyloidogenic processing in Alzheimer’s disease in the presence of SORLA. Mol BioSyst 12:1468–1477. doi:10.1039/c5mb00741k
Alexopoulos P, Guo LH, Kratzer M, Westerteicher C, Kurz A, Perneczky R (2011) Impact of SORL1 single nucleotide polymorphisms on Alzheimer’s disease cerebrospinal fluid markers. Dement Geriatr Cogn Disord 32:164–170. doi:10.1159/000332017
Alexopoulos P, Guo LH, Tsolakidou A, Kratzer M, Grimmer T, Westerteicher C, Jiang M, Bujo H, Diehl-Schmid J, Kurz A et al (2012) Interrelations between CSF soluble AbetaPPbeta, amyloid-beta 1-42, SORL1, and tau levels in Alzheimer’s disease. J Alzheimers Dis 28:543–552. doi:10.3233/JAD-2011-110983
Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X et al (2005) Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci USA 102:13461–13466. doi:10.1073/pnas.0503689102
Andersen OM, Schmidt V, Spoelgen R, Gliemann J, Behlke J, Galatis D, McKinstry WJ, Parker MW, Masters CL, Hyman BT et al (2006) Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11. Biochemistry 45:2618–2628. doi:10.1021/bi052120v
Andrews SJ, Das D, Cherbuin N, Anstey KJ, Easteal S (2016) Association of genetic risk factors with cognitive decline: the PATH through life project. Neurobiol Aging 41:150–158. doi:10.1016/j.neurobiolaging.2016.02.016
Annunziata I, Patterson A, Helton D, Hu H, Moshiach S, Gomero E, Nixon R, d’Azzo A (2013) Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-beta secretion via deregulated lysosomal exocytosis. Nat Commun 4:2734. doi:10.1038/ncomms3734
Bayer TA, Wirths O (2011) Intraneuronal Abeta as a trigger for neuron loss: can this be translated into human pathology? Biochem Soc Trans 39:857–861. doi:10.1042/BST0390857
Beecham GW, Hamilton K, Naj AC, Martin ER, Huentelman M, Myers AJ, Corneveaux JJ, Hardy J, Vonsattel JP, Younkin SG et al (2014) Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias. PLoS Genet 10:e1004606. doi:10.1371/journal.pgen.1004606
Birnbaum RY, Patwardhan RP, Kim MJ, Findlay GM, Martin B, Zhao J, Bell RJ, Smith RP, Ku AA, Shendure J et al (2014) Systematic dissection of coding exons at single nucleotide resolution supports an additional role in cell-specific transcriptional regulation. PLoS Genet 10:e1004592. doi:10.1371/journal.pgen.1004592
Burgert T, Schmidt V, Caglayan S, Lin F, Fuchtbauer A, Fuchtbauer EM, Nykjaer A, Carlo AS, Willnow TE (2013) SORLA-dependent and -independent functions for PACS1 in control of amyloidogenic processes. Mol Cell Biol 33:4308–4320. doi:10.1128/MCB.00628-13
Caglayan S, Bauerfeind A, Schmidt V, Carlo AS, Prabakaran T, Hubner N, Willnow TE (2012) Identification of Alzheimer disease risk genotype that predicts efficiency of SORL1 expression in the brain. Arch Neurol 69:373–379. doi:10.1001/archneurol.2011.788
Caglayan S, Takagi-Niidome S, Liao F, Carlo AS, Schmidt V, Burgert T, Kitago Y, Fuchtbauer EM, Fuchtbauer A, Holtzman DM et al (2014) Lysosomal sorting of amyloid-beta by the SORLA receptor is impaired by a familial Alzheimer’s disease mutation. Sci Trans Med 6:223ra220. doi:10.1126/scitranslmed.3007747
Cai HB, Wang YS, McCarthy D, Wen HJ, Borchelt DR, Price DL, Wong PC (2001) BACE1 is the major beta-secretase for generation of A beta peptides by neurons. Nat Neurosci 4:233–234. doi:10.1038/85064
Camargo LM, Zhang XD, Loerch P, Caceres RM, Marine SD, Uva P, Ferrer M, de Rinaldis E, Stone DJ, Majercak J et al (2015) Pathway-based analysis of genome-wide siRNA screens reveals the regulatory landscape of APP processing. PLoS One 10:e0115369. doi:10.1371/journal.pone.0115369
Chen Y, Peng Y, Che P, Gannon M, Liu Y, Li L, Bu G, van Groen T, Jiao K, Wang Q (2014) alpha(2A) adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction. Proc Natl Acad Sci USA 111:17296–17301. doi:10.1073/pnas.1409513111
Ciarlo E, Massone S, Penna I, Nizzari M, Gigoni A, Dieci G, Russo C, Florio T, Cancedda R, Pagano A (2013) An intronic ncRNA-dependent regulation of SORL1 expression affecting Abeta formation is upregulated in post-mortem Alzheimer’s disease brain samples. Dis Model Mech 6:424–433. doi:10.1242/dmm.009761
Citron M (2010) Alzheimer’s disease: strategies for disease modification. Nat Rev Drug Discov 9:387–398. doi:10.1038/nrd2896
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923
Cuenco KT, Lunetta KL, Baldwin CT, McKee AC, Guo J, Cupples LA, Green RC, St George-Hyslop PH, Chui H, DeCarli C et al (2008) Association of distinct variants in SORL1 with cerebrovascular and neurodegenerative changes related to Alzheimer disease. Arch Neurol 65:1640–1648. doi:10.1001/archneur.65.12.1640
De Strooper B, Vassar R, Golde T (2010) The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 6:99–107. doi:10.1038/nrneurol.2009.218
Dodson SE, Andersen OM, Karmali V, Fritz JJ, Cheng D, Peng J, Levey AI, Willnow TE, Lah JJ (2008) Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: evidence for a proximal role in Alzheimer’s disease. J Neurosci 28:12877–12886. doi:10.1523/JNEUROSCI.4582-08.2008
Dumanis SB, Burgert T, Caglayan S, Fuchtbauer A, Fuchtbauer EM, Schmidt V, Willnow TE (2015) Distinct functions for anterograde and retrograde sorting of SORLA in amyloidogenic processes in the brain. J Neurosci 35:12703–12713. doi:10.1523/JNEUROSCI.0427-15.2015
Elias-Sonnenschein LS, Helisalmi S, Natunen T, Hall A, Paajanen T, Herukka SK, Laitinen M, Remes AM, Koivisto AM, Mattila KM et al (2013) Genetic loci associated with Alzheimer’s disease and cerebrospinal fluid biomarkers in a Finnish case-control cohort. PLoS One 8:e59676. doi:10.1371/journal.pone.0059676
Felsky D, Szeszko P, Yu L, Honer WG, De Jager PL, Schneider JA, Malhotra AK, Lencz T, Ikuta T, Pipitone J et al (2014) The SORL1 gene and convergent neural risk for Alzheimer’s disease across the human lifespan. Mol Psychiatry 19:1125–1132. doi:10.1038/mp.2013.142
Fjorback AW, Seaman M, Gustafsen C, Mehmedbasic A, Gokool S, Wu C, Militz D, Schmidt V, Madsen P, Nyengaard JR et al (2012) Retromer binds the FANSHY sorting Motif in SorLA to regulate amyloid precursor protein sorting and processing. J Neurosci 32:1467–1480. doi:10.1523/JNEUROSCI.2272-11.2012
Glerup S, Lume M, Olsen D, Nyengaard JR, Vaegter CB, Gustafsen C, Christensen EI, Kjolby M, Hay-Schmidt A, Bender D et al (2013) SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRalpha1 and RET. Cell Rep 3:186–199. doi:10.1016/j.celrep.2012.12.011
Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG (1992) Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255:728–730
Grear KE, Ling IF, Simpson JF, Furman JL, Simmons CR, Peterson SL, Schmitt FA, Markesbery WR, Liu Q, Crook JE et al (2009) Expression of SORL1 and a novel SORL1 splice variant in normal and Alzheimers disease brain. Mol Neurodegener 4:46. doi:10.1186/1750-1326-4-46
Guerreiro RJ, Gustafson DR, Hardy J (2012) The genetic architecture of Alzheimer’s disease: beyond APP, PSENs and APOE. Neurobiol Aging 33:437–456. doi:10.1016/j.neurobiolaging.2010.03.025
Guo LH, Westerteicher C, Wang XH, Kratzer M, Tsolakidou A, Jiang M, Grimmer T, Laws SM, Alexopoulos P, Bujo H et al (2012) SORL1 genetic variants and cerebrospinal fluid biomarkers of Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 262:529–534. doi:10.1007/s00406-012-0295-x
Haass C, Koo EH, Mellon A, Hung AY, Selkoe DJ (1992) Targeting of cell-surface beta-amyloid precursor protein to lysosomes—alternative processing into amyloid-bearing fragments. Nature 357:500–503. doi:10.1038/357500a0
Hampe W, Riedel IB, Lintzel J, Bader CO, Franke I, Schaller HC (2000) Ectodomain shedding, translocation and synthesis of SorLA are stimulated by its ligand head activator. J Cell Sci 113(Pt 24):4475–4485
Hardy JA, Higgins GA (1992) Alzheimers-disease—the amyloid cascade hypothesis. Science 256:184–185. doi:10.1126/Science.1566067
Hermey G, Sjogaard SS, Petersen CM, Nykjaer A, Gliemann J (2006) Tumour necrosis factor alpha-converting enzyme mediates ectodomain shedding of Vps10p-domain receptor family members. Biochem J 395:285–293. doi:10.1042/BJ20051364
Herskowitz JH, Offe K, Deshpande A, Kahn RA, Levey AI, Lah JJ (2012) GGA1-mediated endocytic traffic of LR11/SorLA alters APP intracellular distribution and amyloid-beta production. Mol Biol Cell 23:2645–2657. doi:10.1091/mbc.E12-01-0014
Herskowitz JH, Seyfried NT, Gearing M, Kahn RA, Peng JM, Levey AI, Lah JJ (2011) Rho Kinase II phosphorylation of the lipoprotein receptor LR11/SORLA alters amyloid-beta production. J Biol Chem 286:6117–6127. doi:10.1074/Jbc.M110.167239
Hirayama S, Bujo H, Yamazaki H, Kanaki T, Takahashi K, Kobayashi J, Schneider WJ, Saito Y (2000) Differential expression of LR11 during proliferation and differentiation of cultured neuroblastoma cells. Biochem Biophys Res Commun 275:365–373. doi:10.1006/bbrc.2000.3312
Huang CC, Liu ME, Kao HW, Chou KH, Yang AC, Wang YH, Chen TR, Tsai SJ, Lin CP (2016) Effect of Alzheimer’s disease risk variant rs3824968 at SORL1 on regional gray matter volume and age-related interaction in adult lifespan. Sci Rep 6:23362. doi:10.1038/srep23362
Ikeuchi T, Hirayama S, Miida T, Fukamachi I, Tokutake T, Ebinuma H, Takubo K, Kaneko H, Kasuga K, Kakita A et al (2010) Increased levels of soluble LR11 in cerebrospinal fluid of patients with Alzheimer disease. Dement Geriatr Cogn Disord 30:28–32. doi:10.1159/000315539
Jacobsen L, Madsen P, Jacobsen C, Nielsen MS, Gliemann J, Petersen CM (2001) Activation and functional characterization of the mosaic receptor SorLA/LR11. J Biol Chem 276:22788–22796. doi:10.1074/jbc.M100857200
Jacobsen L, Madsen P, Moestrup SK, Lund AH, Tommerup N, Nykjaer A, Sottrup-Jensen L, Gliemann J, Petersen CM (1996) Molecular characterization of a novel human hybrid-type receptor that binds the alpha2-macroglobulin receptor-associated protein. J Biol Chem 271:31379–31383
Jacobsen L, Madsen P, Nielsen MS, Geraerts WP, Gliemann J, Smit AB, Petersen CM (2002) The sorLA cytoplasmic domain interacts with GGA1 and -2 and defines minimum requirements for GGA binding. FEBS Lett 511:155–158
Jin C, Liu X, Zhang F, Wu Y, Yuan J, Zhu J, Zhang F, Wang G, Cheng Z (2013) An updated meta-analysis of the association between SORL1 variants and the risk for sporadic Alzheimer’s disease. J Alzheimers Dis 37:429–437. doi:10.3233/JAD-130533
Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10:U698–U1600. doi:10.1038/Nrd3505
Kitago Y, Nagae M, Nakata Z, Yagi-Utsumi M, Takagi-Niidome S, Mihara E, Nogi T, Kato K, Takagi J (2015) Structural basis for amyloidogenic peptide recognition by sorLA. Nat Struct Mol Biol 22:199–206. doi:10.1038/nsmb.2954
Kolsch H, Jessen F, Wiltfang J, Lewczuk P, Dichgans M, Kornhuber J, Frolich L, Heuser I, Peters O, Schulz JB et al (2008) Influence of SORL1 gene variants: association with CSF amyloid-beta products in probable Alzheimer’s disease. Neurosci Lett 440:68–71. doi:10.1016/j.neulet.2008.05.049
Kolsch H, Jessen F, Wiltfang J, Lewczuk P, Dichgans M, Teipel SJ, Kornhuber J, Frolich L, Heuser I, Peters O et al (2009) Association of SORL1 gene variants with Alzheimer’s disease. Brain Res 1264:1–6. doi:10.1016/j.brainres.2009.01.044
Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, Kremmer E, Rossner S, Lichtenthaler SF (2010) ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J 29:3020–3032. doi:10.1038/Emboj.2010.167
La Rosa LR, Perrone L, Nielsen MS, Calissano P, Andersen OM, Matrone C (2015) Y682G mutation of amyloid precursor protein promotes endo-lysosomal dysfunction by disrupting APP-SorLA interaction. Front Cell Neurosci 9:109. doi:10.3389/fncel.2015.00109
Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45:1452–1458. doi:10.1038/ng.2802
Lane RF, Gatson JW, Small SA, Ehrlich ME, Gandy S (2010) Protein kinase C and rho activated coiled coil protein kinase 2 (ROCK2) modulate Alzheimer’s APP metabolism and phosphorylation of the Vps10-domain protein, SorL1. Mol Neurodegener 5:62. doi:10.1186/1750-1326-5-62
Lao A, Schmidt V, Schmitz Y, Willnow TE, Wolkenhauer O (2012) Multi-compartmental modeling of SORLA’s influence on amyloidogenic processing in Alzheimer’s disease. BMC Syst Biol 6:74. doi:10.1186/1752-0509-6-74
Larsen JV, Kristensen AM, Pallesen LT, Bauer J, Vaegter CB, Nielsen MS, Madsen P, Petersen CM (2016) Cytokine-like factor 1, an essential facilitator of cardiotrophin-like cytokine: ciliary neurotrophic factor receptor alpha signaling and sorLA-mediated turnover. Mol Cell Biol 36:1272–1286. doi:10.1128/MCB.00917-15
Louwersheimer E, Ramirez A, Cruchaga C, Becker T, Kornhuber J, Peters O, Heilmann S, Wiltfang J, Jessen F, Visser PJ et al (2015) Influence of genetic variants in SORL1 gene on the manifestation of Alzheimer’s disease. Neurobiol Aging 36(1605):e1613–e1620. doi:10.1016/j.neurobiolaging.2014.12.007
Ma QL, Galasko DR, Ringman JM, Vinters HV, Edland SD, Pomakian J, Ubeda OJ, Rosario ER, Teter B, Frautschy SA et al (2009) Reduction of SorLA/LR11, a sorting protein limiting beta-amyloid production, in alzheimer disease cerebrospinal fluid. Arch Neurol 66:448–457. doi:10.1001/archneurol.2009.22
Ma QL, Teter B, Ubeda OJ, Morihara T, Dhoot D, Nyby MD, Tuck ML, Frautschy SA, Cole GM (2007) Omega-3 fatty acid docosahexaenoic acid increases SorLA/LR11, a sorting protein with reduced expression in sporadic Alzheimer’s disease (AD): relevance to AD prevention. J Neurosci 27:14299–14307. doi:10.1523/JNEUROSCI.3593-07.2007
Marcusson EG, Horazdovsky BF, Cereghino JL, Gharakhanian E, Emr SD (1994) The sorting receptor for yeast vacuolar carboxypeptidase Y is encoded by the VPS10 gene. Cell 77:579–586
McCarthy JJ, Saith S, Linnertz C, Burke JR, Hulette CM, Welsh-Bohmer KA, Chiba-Falek O (2012) The Alzheimer’s associated 5′ region of the SORL1 gene cis regulates SORL1 transcripts expression. Neurobiol Aging 33(1485):e1481–e1488. doi:10.1016/j.neurobiolaging.2010.10.004
Mecozzi VJ, Berman DE, Simoes S, Vetanovetz C, Awal MR, Patel VM, Schneider RT, Petsko GA, Ringe D, Small SA (2014) Pharmacological chaperones stabilize retromer to limit APP processing. Nat Chem Biol 10:443–449. doi:10.1038/nchembio.1508
Mehmedbasic A, Christensen SK, Nilsson J, Ruetschi U, Gustafsen C, Poulsen AS, Rasmussen RW, Fjorback AN, Larson G, Andersen OM (2015) SorLA complement-type repeat domains protect the amyloid precursor protein against processing. J Biol Chem 290:3359–3376. doi:10.1074/jbc.M114.619940
Miyashita A, Koike A, Jun G, Wang LS, Takahashi S, Matsubara E, Kawarabayashi T, Shoji M, Tomita N, Arai H et al (2013) SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PloS one 8:e58618. doi:10.1371/journal.pone.0058618
Motoi Y, Aizawa T, Haga S, Nakamura S, Namba Y, Ikeda K (1999) Neuronal localization of a novel mosaic apolipoprotein E receptor, LR11, in rat and human brain. Brain Res 833:209–215
Nettiksimmons J, Tranah G, Evans DS, Yokoyama JS, Yaffe K (2016) Gene-based aggregate SNP associations between candidate AD genes and cognitive decline. Age 38:41. doi:10.1007/s11357-016-9885-2
Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B, Rousseau S, Richard AC, Rovelet-Lecrux A, Le Guennec K et al (2016) SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease. Mol Psychiatry 21(6):831–836. doi:10.1038/mp.2015.121
Nielsen MS, Gustafsen C, Madsen P, Nyengaard JR, Hermey G, Bakke O, Mari M, Schu P, Pohlmann R, Dennes A et al (2007) Sorting by the cytoplasmic domain of the amyloid precursor protein binding receptor SorLA. Mol Cell Biol 27:6842–6851. doi:10.1128/MCB.00815-07
Nishii K, Nakaseko C, Jiang M, Shimizu N, Takeuchi M, Schneider WJ, Bujo H (2013) The soluble form of LR11 protein is a regulator of hypoxia-induced, urokinase-type plasminogen activator receptor (uPAR)-mediated adhesion of immature hematological cells. J Biol Chem 288:11877–11886. doi:10.1074/jbc.M112.442491
Offe K, Dodson SE, Shoemaker JT, Fritz JJ, Gearing M, Levey AI, Lah JJ (2006) The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments. J Neurosci 26:1596–1603. doi:10.1523/JNEUROSCI.4946-05.2006
Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S, Legallic S, Paquet C, Bombois S, Pariente J et al (2012) High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry 17:875–879. doi:10.1038/Mp.2012.15
Quistgaard EM, Madsen P, Groftehauge MK, Nissen P, Petersen CM, Thirup SS (2009) Ligands bind to Sortilin in the tunnel of a ten-bladed beta-propeller domain. Nat Struct Mol Biol 16:96–98. doi:10.1038/nsmb.1543
Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, Simons K (2006) Alzheimer’s disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci USA 103:11172–11177. doi:10.1073/pnas.0603838103
Rajendran L, Schneider A, Schlechtingen G, Weidlich S, Ries J, Braxmeier T, Schwille P, Schulz JB, Schroeder C, Simons M et al (2008) Efficient inhibition of the Alzheimer’s disease beta-secretase by membrane targeting. Science 320:520–523. doi:10.1126/science.1156609
Reiche J, Theilig F, Rafiqi FH, Carlo AS, Militz D, Mutig K, Todiras M, Christensen EI, Ellison DH, Bader M et al (2010) SORLA/SORL1 functionally interacts with SPAK to control renal activation of Na(+)-K(+)-Cl(−) cotransporter 2. Mol Cell Biol 30:3027–3037. doi:10.1128/MCB.01560-09
Reitz C, Cheng R, Rogaeva E, Lee JH, Tokuhiro S, Zou F, Bettens K, Sleegers K, Tan EK, Kimura R et al (2011) Meta-analysis of the association between variants in SORL1 and Alzheimer disease. Arch Neurol 68:99–106. doi:10.1001/archneurol.2010.346
Reynolds CA, Zavala C, Gatz M, Vie L, Johansson B, Malmberg B, Ingelsson E, Prince JA, Pedersen NL (2013) Sortilin receptor 1 predicts longitudinal cognitive change. Neurobiol Aging 34(1710):e1711–e1718. doi:10.1016/j.neurobiolaging.2012.12.006
Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H et al (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39:168–177. doi:10.1038/ng1943
Rohe M, Carlo AS, Breyhan H, Sporbert A, Militz D, Schmidt V, Wozny C, Harmeier A, Erdmann B, Bales KR et al (2008) Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis. J Biol Chem 283:14826–14834. doi:10.1074/jbc.M710574200
Rohe M, Hartl D, Fjorback AN, Klose J, Willnow TE (2013) SORLA-mediated trafficking of TrkB enhances the response of neurons to BDNF. PLoS One 8:e72164. doi:10.1371/journal.pone.0072164
Rohe M, Synowitz M, Glass R, Paul SM, Nykjaer A, Willnow TE (2009) Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression. J Neurosci 29:15472–15478. doi:10.1523/JNEUROSCI.3960-09.2009
Rudenko G, Henry L, Henderson K, Ichtchenko K, Brown MS, Goldstein JL, Deisenhofer J (2002) Structure of the LDL receptor extracellular domain at endosomal pH. Science 298:2353–2358. doi:10.1126/science.1078124
Sannerud R, Annaert W (2009) Trafficking, a key player in regulated intramembrane proteolysis. Semin Cell Dev Biol 20:183–190. doi:10.1016/J.Semcdb.2008.11.004
Sannerud R, Declerck I, Peric A, Raemaekers T, Menendez G, Zhou L, Veerle B, Coen K, Munck S, De Strooper B et al (2011) ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1. Proc Natl Acad Sci USA 108:E559–E568. doi:10.1073/pnas.1100745108
Scherzer CR, Offe K, Gearing M, Rees HD, Fang G, Heilman CJ, Schaller C, Bujo H, Levey AI, Lah JJ (2004) Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch Neurol 61:1200–1205. doi:10.1001/archneur.61.8.1200
Schmidt V, Baum K, Lao A, Rateitschak K, Schmitz Y, Teichmann A, Wiesner B, Petersen CM, Nykjaer A, Wolf J et al (2012) Quantitative modelling of amyloidogenic processing and its influence by SORLA in Alzheimer’s disease. EMBO J 31:187–200. doi:10.1038/emboj.2011.352
Schmidt V, Sporbert A, Rohe M, Reimer T, Rehm A, Andersen OM, Willnow TE (2007) SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1. J Biol Chem 282:32956–32964. doi:10.1074/jbc.M705073200
Seaman MN (2004) Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J Cell Biol 165:111–122. doi:10.1083/jcb.200312034
Seaman MN (2007) Identification of a novel conserved sorting motif required for retromer-mediated endosome-to-TGN retrieval. J Cell Sci 120:2378–2389
Selkoe DJ (2011) Alzheimer’s Disease. Cold Spring Harbor Perspect Biol 3(7):a004457. doi:10.1101/cshperspect.a004457
Selkoe DJ (1991) The molecular pathology of Alzheimer’s disease. Neuron 6:487–498
Spoelgen R, von Arnim CA, Thomas AV, Peltan ID, Koker M, Deng A, Irizarry MC, Andersen OM, Willnow TE, Hyman BT (2006) Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme. J Neurosci 26:418–428. doi:10.1523/JNEUROSCI.3882-05.2006
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90:1977–1981
Tsolakidou A, Alexopoulos P, Guo LH, Grimmer T, Westerteicher C, Kratzer M, Jiang M, Bujo H, Roselli F, Leante MR et al (2013) beta-Site amyloid precursor protein-cleaving enzyme 1 activity is related to cerebrospinal fluid concentrations of sortilin-related receptor with A-type repeats, soluble amyloid precursor protein, and tau. Alzheimers Dement 9:386–391. doi:10.1016/j.jalz.2012.01.015
Vardarajan BN, Zhang Y, Lee JH, Cheng R, Bohm C, Ghani M, Reitz C, Reyes-Dumeyer D, Shen Y, Rogaeva E et al (2015) Coding mutations in SORL1 and Alzheimer disease. Ann Neurol 77:215–227. doi:10.1002/ana.24305
Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R et al (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741
Verheijen J, Van den Bossche T, van der Zee J, Engelborghs S, Sanchez-Valle R, Llado A, Graff C, Thonberg H, Pastor P, Ortega-Cubero S et al (2016) A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease. Acta Neuropathol 132(2):213–224. doi:10.1007/s00401-016-1566-9
Walsh DM, Selkoe DJ (2007) A beta oligomers—a decade of discovery. J Neurochem 101:1172–1184. doi:10.1111/j.1471-4159.2006.04426.x
Wang Z, Lei H, Zheng M, Li Y, Cui Y, Hao F (2015) Meta-analysis of the association between Alzheimer disease and variants in GAB2, PICALM, and SORL1. Mol Neurobiol. doi:10.1007/s12035-015-9546-y
Whittle AJ, Jiang M, Peirce V, Relat J, Virtue S, Ebinuma H, Fukamachi I, Yamaguchi T, Takahashi M, Murano T et al (2015) Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans. Nat Commun 6:8951. doi:10.1038/ncomms9951
Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M, Kootar S, Hornburg D, Evans LD, Moore S, Daria A et al (2015) eta-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature 526:443–447. doi:10.1038/nature14864
Willnow TE, Andersen OM (2013) Sorting receptor SORLA—a trafficking path to avoid Alzheimer disease. J Cell Sci 126:2751–2760. doi:10.1242/jcs.125393
Willnow TE, Petersen CM, Nykjaer A (2008) VPS10P-domain receptors—regulators of neuronal viability and function. Nat Rev Neurosci 9:899–909. doi:10.1038/nrn2516
Yamazaki H, Bujo H, Kusunoki J, Seimiya K, Kanaki T, Morisaki N, Schneider WJ, Saito Y (1996) Elements of neural adhesion molecules and a yeast vacuolar protein sorting receptor are present in a novel mammalian low density lipoprotein receptor family member. J Biol Chem 271:24761–24768
Young JE, Boulanger-Weill J, Williams DA, Woodruff G, Buen F, Revilla AC, Herrera C, Israel MA, Yuan SH, Edland SD et al (2015) Elucidating molecular phenotypes caused by the SORL1 Alzheimer’s disease genetic risk factor using human induced pluripotent stem cells. Cell Stem Cell 16:373–385. doi:10.1016/j.stem.2015.02.004
Yu L, Chibnik LB, Srivastava GP, Pochet N, Yang J, Xu J, Kozubek J, Obholzer N, Leurgans SE, Schneider JA et al (2015) Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease. JAMA Neurol 72:15–24. doi:10.1001/jamaneurol.2014.3049
Acknowledgments
Work in the authors’ laboratories was supported by grants from the European Research Council (BeyOND), the Berlin Institute of Health, and the Helmholtz Association (International Research Group Program and iCEMED) (to TW), and by grants from the Danish National Research council, the Lundbeck Foundation, and the Novo Nordisk Foundation (to OA).
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Cite this article
Andersen, O.M., Rudolph, IM. & Willnow, T.E. Risk factor SORL1: from genetic association to functional validation in Alzheimer’s disease. Acta Neuropathol 132, 653–665 (2016). https://doi.org/10.1007/s00401-016-1615-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-016-1615-4