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Original Contribution |

Reduction of SorLA/LR11, a Sorting Protein Limiting β-Amyloid Production, in Alzheimer Disease Cerebrospinal Fluid FREE

Qiu-Lan Ma, MD, PhD; Douglas R. Galasko, MD; John M. Ringman, MD; Harry V. Vinters, MD; Steven D. Edland, PhD; Justine Pomakian, MPH; Oliver J. Ubeda, BS; Emily R. Rosario, PhD; Bruce Teter, PhD; Sally A. Frautschy, PhD; Greg M. Cole, PhD
[+] Author Affiliations

Author Affiliations: Departments of Medicine (Drs Ma, Rosario, Teter, Frautschy, and Cole and Mr Ubeda), Neurology (Drs Ringman, Vinters, Pomakian, Frautschy, and Cole), and Pathology and Laboratory Medicine (Drs Vinters and Pomakian), University of California, Los Angeles, Department of Neuroscience, University of California, San Diego (Drs Galasko and Edland), and Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs (VA) Healthcare System, VA Medical Center, North Hills, California (Drs Ma, Rosario, Teter, Frautschy, and Cole and Mr Ubeda).


Arch Neurol. 2009;66(4):448-457. doi:10.1001/archneurol.2009.22.
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Published online

Background  The sortilin-related receptor SorLA/LR11 (LR11) is a transmembrane neuronal sorting protein that reduces β-amyloid precursor protein trafficking to secretases, notably BACE1 that generates β-amyloid, the principal component of senile plaques in Alzheimer disease (AD). LR11 protein is reduced in patients with late-onset AD, and LR11 polymorphisms have been associated with late-onset AD.

Objective  T o detect soluble LR11 and APP in cerebrospinal fluid (CSF) from patients with AD and control subjects, as (like β-amyloid precursor protein) LR11 is cleaved near the membrane to release a large N-terminal fragment that is secreted to media from cultured cells.

Design  Case-control study.

Setting  Academic research.

Participants  Patients with AD and control subjects.

Main Outcome Measures  We evaluated CSF LR11, β-amyloid precursor protein, and apolipoprotein E levels by Western blot in lumbar and postmortem CSF samples.

Results  LR11 levels were detectable and stable during 6 months in the CSF of patients with AD. LR11 levels were significantly reduced in lumbar samples from patients with mild to moderate probable AD, as well as in ventricular CSF from patients with autopsy-confirmed AD (predominantly Braak stage III-IV). Bivariate analysis with β-amyloid 42 and LR11 levels improved diagnostic specificity for AD. Reduced LR11 levels are significantly correlated with soluble β-amyloid precursor protein but not apolipoprotein E levels.

Conclusion  Reduced LR11 levels in CSF of patients with AD may have potential as a diagnostic biomarker for patients with LR11 deficits that promote β-amyloid production or as an index of therapeutic response in late-onset AD.

Figures in this Article

The neuronal sortilin-related receptor SorLA/LR11 (LR11), a member of the apolipoprotein E (ApoE) and low-density lipoprotein receptor family, functions as a sorting and trafficking protein, guiding β-amyloid precursor protein (APP) into the recycling endosome pathways that lead to production of β-amyloid peptide (Aβ).1 In 2007, LR11 was shown to reduce Aβ production and was found to be a candidate genetic risk factor for late-onset Alzheimer disease (LOAD),2 the most common cause of dementia in aged populations. Genetic polymorphisms associated with increased Alzheimer disease (AD) risk and with reduced LR11 expression were found in approximately 15% of AD cases in several but not all population-based investigations.3 Furthermore, neuronal LR11 expression is reduced in brain tissue from patients with LOAD4,5 but not from patients with early-onset familial AD, in which overproduction of Aβ42 is thought to be causative.6 In addition, subjects having mild cognitive impairment (MCI) with low brain levels of LR11 were significantly more cognitively impaired than subjects with high brain levels of LR11. Reduced LR11 levels occur early, increase with disease severity, and may predict progression to AD in a subgroup of individuals with MCI.7 Collectively, these data argue that, whatever their cause, LR11 deficits in LOAD occur early and are not simply secondary to pathologic changes. Furthermore, because they can be predicted to increase Aβ42 production, LR11 deficits are likely to contribute to pathogenesis and could be a useful target of a diagnostic biomarker or therapeutic intervention.

The selective reduction of Aβ42 in cerebrospinal fluid (CSF) of patients with AD has been widely used as a biomarker to increase diagnostic accuracy. However, deposition of Aβ42 in the brain or its reduction in CSF occurs in other non-AD dementias such as dementia with Lewy bodies8 and Parkinson disease dementia.9 Therefore, the differential diagnosis of dementia based on established clinical criteria and informed by reduced Aβ42 levels in CSF is still difficult to assess in standard practice. Other widely used CSF biomarkers for AD are elevated total tau (T-tau) or phosphorylated-tau (P-tau) levels. Cerebrospinal fluid levels of T-tau presumably reflect the intensity of neurodegeneration. There is no consensus whether any tau phosphorylation sites are specific for AD and not found in other tauopathies.10 Elevated CSF T-tau level is also found in vascular dementia11 and in Creutzfeldt-Jakob disease.12 Therefore, while useful, CSF Aβ and tau levels have limitations in the differential diagnosis of dementia.13,14 It remains a challenge to identify an ideal biomarker for AD that is directly linked to the primary mechanism of the disease and that can be used to monitor disease progression.

Although LR11 has a single transmembrane domain, it is endoproteolytically cleaved near the plasma membrane C-terminus, so that low levels of a large (approximately 250 kD) soluble LR11 N-terminal piece (LR11s) can be observed in conditioned media from 3 different human cell lines, including NT2 cells (neurogenic human embryonal carcinoma cells), BON cells (a pancreatic neuroendocrine tumor cell line),15 and SH-SY5Y human neuroblastoma cells.16 Therefore, we hypothesized that LR11 might be secreted into CSF and reduced in patients with AD. To test this hypothesis, we examined LR11 levels by Western blot in the lumbar CSF of patients with mild to moderate AD (mean Mini-Mental State Examination score, 24) and in ventricular CSF of patients with autopsy-confirmed AD and compared them with CSF of age-matched healthy persons and patients with non-AD dementias as neurologic control subjects.

PATIENTS WITH AD AND CONTROLS

The diagnosis of probable AD was established according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria.17 Cognitive status was examined by multiple measures, including the Mini-Mental State Examination.18 Lumbar CSF samples were collected from 2 different research groups by lumbar puncture under standardized conditions, and aliquots were frozen at −80°C until used. The first group included 26 subjects (13 patients with AD and 13 age-comparable cognitively intact controls) enrolled at the University of California, San Diego AD research center site. The mean Mini-Mental State Examination scores were 24 (range, 17-28) for the patients with AD and 29 (range, 27-30) for the controls (Table 1). The second group included 17 patients with AD having serial CSF samples collected at the University of California, Los Angeles AD research center. In this group, the second CSF sample was collected 6 months after the first. The stability of our measures (LR11, secretase-cleaved soluble APP [sAPP], and ApoE) was investigated in these serial samples from patients with AD. To assess the usefulness of LR11 as a biomarker relative to Aβ42 and tau, we increased sample numbers in the first group (a total of 19 patients with AD and 18 age-comparable cognitively intact controls) and measured T-tau, P-tau, and Aβ42 levels. For all subjects, LR11, sAPP, and ApoE levels were measured using Western blot at the University of California, Los Angeles. Levels of CSF T-tau and Aβ42 were assessed using a commercially available system (Luminex xMAP; Invitrogen, Carlsbad, California).

Table Graphic Jump LocationTable 1. Clinical Characteristics of Cerebrospinal Fluid Sample Donors
PATIENTS WITH AUTOPSY-CONFIRMED AD AND CONTROLS

Postmortem CSF samples were collected from 10 patients with autopsy-confirmed AD, 5 controls with non-AD dementias, and 5 age-matched healthy individuals based on autopsy reports from one of us (H.V.V.) at the University of California, Los Angeles AD research center. For the pathologic diagnoses of AD, plaque density was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria,19 and neurofibrillary tangles were evaluated using the criteria by Braak and Braak.20 The following 3 types of plaques were identified and counted: (1) diffuse plaques (a neuropil deposition of finely granular material on Bielschowsky-stained sections), (2) dense core plaques (a neuropil deposition of compact argyrophilic material on Bielschowsky-stained sections), and (3) neuritic plaques (the presence of dystrophic neurites arranged radially and forming a discrete spherical lesion averaging about 30 mm in diameter).21,22 Neuritic plaques were counted on tau-immunostained sections. Plaque counts were normalized and expressed as the number of counts per millimeter squared. The number of each type of plaque was also characterized according to the CERAD rating scheme as none, sparse (1-5 per 3100 field), moderate (6-15 per 3100 field), or frequent (>15 per 3100 field).19,22 The score of the neocortical region with the highest count was used as the overall score for each subject (Table 2). CERAD criteria19 and Braak stage20 were combined to give an estimate of the likelihood that AD pathologic changes underlie dementia using criteria of the National Institute on Aging and the Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease.23 Autopsy-confirmed AD stage was typically intermediate (CERAD19 moderate plaques and Braak stage III-IV). Dementia with Lewy bodies was diagnosed according to the pathologic criteria by Kosaka et al.24 Ventricular CSF was collected during autopsy, and aliquots were frozen at −80°C until used. Patients with AD were a mean (SD) of 83.7 (10.2) years old. The mean (SD) postmortem interval before autopsy was 18.9 (10.4) hours (Table 1).

Table Graphic Jump LocationTable 2. Description of Senile Plaque Densities and Neurofibrillary Tangles and Other Pathologic Characteristics of Cerebrospinal Fluid Samples From Patients With Autopsy-Based Disease and Healthy Control Subjects
WESTERN BLOT

Western blot was performed as described previously.25 In brief, 50 μL of CSF was electrophoresed on 6% tris-glycine gels, and Western blots were stained with anti-LR11 (1:1000 dilution; BD Biosciences, San Jose, California) monoclonal antibody, followed with goat antimouse secondary antibody at 1:50 000 dilution for 1 hour and developed using chemiluminescence (Supersignal; Pierce, Rockford, Illinois) at 1:40 dilution. α-Secretase–cleaved APP (sAPPα) was detected by 6E10 antibody (1:2000 dilution; Signet Laboratories, Inc, Dedham, Massachusetts). After stripping immunoblots, β-secretase–cleaved APP (sAPPβ) was detected by sAPPβ polyclonal rabbit antibody (1:1000 dilution; Covance Development Services Company, Berkeley, California), followed with goat antirabbit secondary antibody at 1:100 000 dilution for 1 hour. Apolipoprotein E was detected by monoclonal mouse ApoE antibody (1:1000 dilution; Chemicon, Temecula, California). Band intensities were scanned and quantified using densitometric software (Molecular Analyst II; Bio-Rad, Hercules, California) and were expressed as arbitrary units. Quantification was performed blind to diagnosis.

HUMAN SH-SY5Y CELL LINES

Human SH-SY5Y neuroblastoma cells were maintained in Dulbecco modified Eagle medium supplemented with 2mM L-glutamine. Using 6-well plates, 5 × 105 cells were plated and grown to 80% confluence at 37°C in an incubator with a humidified 5% carbon dioxide atmosphere. Cultured media were collected for Western blot. Cultured cells were placed on ice, washed, and scraped into a cold phosphate-buffered saline solution, and 3000-rpm microfuge pellets were dissolved in lysis buffer containing protease and phosphatase inhibitors, sonicated, incubated (4°C for 30 minutes), and centrifuged (14 000 rpm for 10 minutes). Supernatants were used for Western blot.

STATISTICAL ANALYSIS

Stability of CSF analyte levels was assessed by Pearson product moment correlation coefficients of serial measures 6 months apart and by paired t tests on 6-month change in CSF levels. Between-group differences in postmortem CSF levels were assessed by analysis of variance, followed by Tukey-Kramer post hoc tests. Bivariate receiver operating characteristic (ROC) curves were constructed using the method by Pepe et al.26 All statistical analyses were performed using commercially available software (StatView 5.0; StatView, Cary, North Carolina) except for the ROC curves and related statistics, which were calculated using a statistical package (ROCR; GNU General Public License, Boston, Massachusetts; http://rocr.bioinf.mpi-sb.mpg.de27)and a statistical programming language (R; R Development Core Team; http://www.R-project.org).

LR11 SECRETION INTO CULTURED MEDIUM IN SH-SY5Y CELLS AND INTO CSF IN HUMAN BRAIN

Hampe et al15 reported that a soluble form of LR11 was secreted into conditioned medium of human NT2 and BON cells. The molecular mass of soluble LR11 seemed slightly less than that of the membrane-bound approximately 250-kD full-length LR11 form, in which the LR11 fragment was about 10 kDa less than the membrane fraction form. Consistent with this study, we found that soluble LR11 is also present in cultured medium from human SH-SY5Y neuroblastoma cells (Figure 1A) and in human CSF (Figure 1B). LR11s in cultured media and in human CSF were slightly smaller than the form found in membrane fractions on 6% gels, suggesting that LR11 could be secreted into culture media or human CSF and detected by Western blot with LR11 antibody.

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Figure 1.

Sortilin-related receptor SorLA/LR11 (LR11) was secreted into culture medium from SH-SY5Y cells and into cerebrospinal fluid (CSF) in human brain. A, Western blot of approximately 250-kD LR11 band in SH-SY5Y cell lysates was slightly larger than the secreted LR11 band found in conditioned media. B, Secreted LR11 band in CSF in human brain is similarly slightly smaller than the LR11 membrane fraction band (lysis buffer extract).

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STABILITY OF LR11 IN CSF OF PATIENTS WITH AD

To determine whether CSF LR11 is stable over time in patients with AD, we examined LR11 from serial CSF samples obtained 6 months apart in a cohort of 17 patients with AD. Western blot showed no difference in the LR11 level between first and second samples in CSF from patients with AD (P =.81 [Figure 2A]). A high correlation between first and second samples of LR11 was observed (r = 0.92, P < .001 [Figure 2B]), suggesting that the level of LR11 is stable within a 6-month time frame in patients with established AD. The relative levels of sAPPα (P =.80), sAPPβ (P =.78), and ApoE (P =.65) also did not show significant differences between first and second samples after a 6-month interval. Similarly, good correlations between the first and second CSF samples were found for sAPPα (P < .001, r = 0.97 [Figure 2C]), sAPPβ (P =.001, r = 0.72 [Figure 2D]), and ApoE (P =.001, r = 0.78 [Figure 2E]).

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Figure 2.

Stability of sortilin-related receptor SorLA/LR11 (LR11) in cerebrospinal fluid (CSF) of patients with Alzheimer disease (AD). A, Western blot showed LR11, secretase-cleaved soluble β-amyloid precursor protein (sAPP), and apolipoprotein E (ApoE) band densities in CSF from a group of patients with AD having lumbar samples repeated after 6 months. The LR11, sAPP, and ApoE levels were highly stable between baseline and subsequent CSF draws. There were no significant differences between first and second CSF levels of LR11 (P = .81), α-secretase–cleaved APP (sAPPα) (P = .80), β-secretase–cleaved APP (sAPPβ) (P = .78), or ApoE (P = .65). Baseline and final CSF levels of LR11 (P < .001, r = 0.92 [B]), sAPPα (P < .001, r = 0.97 [C]), sAPPβ (P = .001, r = 0.72 [D]), and ApoE (P = .001, r = 0.78 [E]) significantly correlated with each other. OD indicates optical density.

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LR11 LEVELS IN CSF OF PATIENTS WITH MILD AD WERE SIGNIFICANTLY DECREASED AND CORRELATED WITH sAPP LEVELS BUT NOT ApoE LEVELS

To determine whether there was any alteration in LR11 protein levels of CSF from patients with AD, we first compared LR11 protein levels in subjects with probable AD with those in cognitively healthy controls by Western blot using a monoclonal antibody against LR11. The specificity of our anti-LR11 was well characterized in vitro by small interfering RNA to LR112 and in vivo using LR11 knockout mice.16 Our results indicated that LR11 levels were significantly decreased in patients having AD compared with healthy controls (P =.03 [Figure 3A and B]). This result is consistent with previous findings that LR11 levels were significantly decreased in brain tissue from patients with LOAD.1,6,28 To further confirm these results, we increased sample numbers (to 19 patients with AD and 18 controls), reran and reanalyzed Western blots for LR11, and measured CSF Aβ42, P-tau, and T-tau levels. The mean LR11 (P =.04) levels remained statistically significantly different between patients with AD and controls in the expanded sample (Table 3). The Aβ42 (P =.003), T-tau (P =.046), and P-tau (P =.04) levels also showed significant differences between patients with AD and controls, suggesting that these patients with AD were typical for the established biomarkers of mild AD.

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Figure 3.

The sortilin-related receptor SorLA/LR11 (LR11) and secretase-cleaved soluble β-amyloid precursor protein (sAPP) levels in cerebrospinal fluid in patients with early Alzheimer disease (AD) were significantly decreased and correlated with the sAPP level but not the apolipoprotein (ApoE) level. A, Western blot showed that levels of LR11, α-secretase–cleaved APP (sAPPα), and β-secretase–cleaved (sAPPβ) significantly decreased in patients having early AD compared with control subjects (CTRLs), while the ApoE level did not show significant changes. β-Actin demonstrated the consistency with equal protein loading. B, Densitometric quantitation of LR11 from A confirmed a difference between patients with AD and CTRLs (P =.03). C, Densitometric quantitation of sAPPβ from A showed that sAPPβ was reduced in patients with AD compared with CTRLs (P =.02). D, Densitometric quantitation of ApoE from A showed that there was no difference in ApoE levels between patients with AD and CTRLs (P =.56). E, The LR11 level significantly correlated with sAPPβ level (P < .001, r =0.72). F, The LR11 level did not correlate with ApoE level (P =.46, r = 0.15). B-F, Open circle indicates CTRLs; solid circle, patients with AD; and OD, optical density.

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Table Graphic Jump LocationTable 3. Summary Statistics for Comparison of LR11, β42-Amyloid, Total Tau, and P-tau Levels in the Expanded Sample

We used ROC curves to characterize the potential discriminant usefulness of LR11, Aß42, T-tau, and P-tau lev els using the sample of 19 patients with AD and 18 controls. The Aβ42 level was the most effective univariate discriminator of AD vs control in our data, with an area under the ROC curve (AUC) of 0.789 compared with 0.661 for LR11 level. Adding T-tau or P-tau level to a bivariate discriminant model with Aβ42 level did not substantively improve the model as measured by AUC, only increasing the AUC to 0.793. In contrast, adding LR11 level increased the AUC to 0.865 (P =.01). The Aβ42/LR11 ROC curve cutoff that correctly identifies 90% of the cases (sensitivity, 0.90) also correctly identifies 81% of the controls (specificity, 0.81) (Figure 4).

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Figure 4.

Combining predictors for classification using the area under the receiver operating characteristic (ROC) curve. A, Univariate β42-amyloid (Aβ42) ROC curve with bivariate (LR11 and Aβ42) ROC curve overlain. Adding LR11 to the discriminant function with Aβ42 improved sensitivity and specificity (area under the ROC curve changes from 0.789 to 0.865, P =.01). B, Univariate Aβ42 ROC curve with bivariate (phosphorylated [P] tau and Aβ42) ROC curve overlain. Adding P-tau did not improve sensitivity and specificity (area under the ROC curve changes from 0.789 to 0.793).

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Because LR11 functions as a neuronal sorting protein that binds APP and regulates APP processing to decrease Aβ production in cultured cells,2,28 we investigated whether there was any change in the sAPP level in CSF of human subjects and its correlation with LR11 level. The results showed that the sAPPβ level was significantly decreased in patients having AD compared with controls (P =.02 [Figure 3C]) and that the sAPPα level had a trend toward a decrease (P =.06, data not shown), consistent with earlier studies.29,30 The reduced sAPPα (P < .001, r = 0.64; data not shown) and sAPPβ (P < .001, r = 0.72) levels significantly correlated with levels of the APP binding partner, LR11 (Figure 3E).

Apolipoprotein E is involved in lipid transport and cholesterol homeostasis as a major component of brain lipoproteins. The presence of the ApoE4 allele is a major risk factor for LOAD,31 and LR11 is a member of the low-density lipoprotein receptor family reported to interact with ApoE.32,33 Therefore, we investigated CSF ApoE levels and their possible correlation with LR11 levels in these subjects. Consistent with previous findings,34 ApoE levels in CSF did not show any significant difference between patients with AD and controls (P =.56 [Figure 3D]). Furthermore, no correlation between the ApoE level and the LR11 level was observed (P =.46, r = 0.15 [Figure 3F]).

LR11 LEVEL BUT NOT ApoE LEVEL WAS SIGNIFICANTLY DECREASED IN POSTMORTEM CSF SAMPLES OF PATIENTS WITH AUTOPSY-CONFIRMED AD

To further confirm the observation that the CSF LR11 level is decreased in patients with AD, we studied postmortem CSF samples of patients with autopsy-confirmed moderate AD. The results showed that LR11 levels in postmortem CSF samples of patients with AD were significantly diminished compared with those of healthy controls or patients with non-AD dementias (P < .05 [Figure 5A and B]). Again, ApoE levels did not show any difference in these 3 groups (Figure 5A and C). These results are comparable to those obtained with lumbar CSF samples from patients with probable AD (Figure 3).

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Figure 5.

The sortilin-related receptor SorLA/LR11 (LR11) levels but not apolipoprotein E (ApoE) levels in postmortem cerebrospinal fluid samples from patients with autopsy-confirmed Alzheimer disease (AD) were significantly decreased. A, Western blot showed that the LR11 level was significantly decreased in patients with AD compared with healthy control subjects (CTRLs) or CTRLs with non-AD dementias (others); ApoE did not show significant differences. Roman numerals after AD indicate Braak stage. B, Densitometric quantification of LR11 from A confirmed a significant difference between patients with AD and healthy CTRLs or others (P < .05). C, Densitometric quantification of ApoE from A showed that there was no difference in ApoE levels between patients with AD and healthy CTRLs or others (P > .05). OD indicates optical density.

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In this study, we report that LR11 protein can be detected and measured in CSF and that levels are significantly reduced in CSF of patients with mild to moderate AD compared with age-matched controls. This reduction was confirmed in postmortem CSF samples of patients with autopsy-proven AD but not in patients with non-AD dementias such as dementia with Lewy bodies, multiple system atrophy, and vascular dementia. Perhaps not surprisingly for an APP binding protein, LR11 level significantly correlated with the sAPPα and sAPPβ levels. Despite being a low-density lipoprotein receptor family member that can bind ApoE, the LR11 level did not correlate with the ApoE level. These findings are consistent with a primary role for LR11 as a neuronal sorting protein rather than as a significant CNS ApoE receptor.

Although the genetic association of LR11 with LOAD remains controversial, LR11 deficits with reductions in LR11 messenger RNA and protein have been a consistent finding in patients with LOAD but not in patients with early-onset familial AD, in which overproduction of Aβ42 is known to be caused by presenilin or APP mutations. This suggests that LR11 loss does not occur simply secondary to pathologic changes and might occur at early disease stages and even before diagnosis. Herein, we found that decreased LR11 levels in CSF occurred at an early stage (in patients with a mean Mini-Mental State Examination score of 24) and was further confirmed in patients having autopsy-proven AD with Braak stage III or IV. Because reduced LR11 levels have been observed in a subgroup of individuals with MCI,7 LR11 deficits in CSF may be detectable in patients with MCI or even earlier stages of AD in a subset of patients at risk for LOAD. Combining the essential function of LR11 in trafficking APP and regulating Aβ production, these data strongly suggest that CSF LR11 levels might be a useful biomarker for LOAD.

LR11 contains a vacuolar protein sorting 10-protein domain involved in protein transport between the plasma membrane, endosomes, and late Golgi compartments.33,35,36 Increased LR11 levels significantly alter the sorting and trafficking of APP to the recycling Golgi and early endosomal compartments, which results in a decrease in Aβ production via the amyloidogenic pathway.1,37 In addition, it has been reported that LR11 sorts APP to intracellular protein complexes (retromers) that traffic APP away from α- and β-secretase.38,39 Retromer trafficking dysfunction can lead to increased APP in the late endosome, an organelle in which BACE activity and Aβ production are maximized.40,41 Reductions of sAPP (including α- and β-sAPP) in CSF of patients with AD have been reported and were initially proposed as a diagnostic marker for AD.29,30,42 However, sAPP deficits have not been widely studied or used as diagnostic markers clinically. In this study, sAPP levels (including sAPPα and sAPPβ) were reduced in CSF of patients with AD. Notably, LR11 levels significantly correlated with those of sAPP. It is possible that this correlation occurs as a result of the binding of LR11 with APP and regulation of its processing. These results may provide a potential explanation for the changes of sAPP level in CSF from patients with AD.

Considering that LR11 is a member of the ApoE receptor family, LR11 could be influenced by ApoE in CSF and vice versa. However, ApoE levels in CSF did not differ between patients with AD and controls and did not correlate with LR11 levels. Any role for LR11 in CNS ApoE metabolism remains hypothetical.

In summary, this study demonstrates that soluble LR11 is significantly reduced in CSF of patients with early AD and correlates with reductions in sAPP but not the ApoE level. Reduced LR11 levels in CSF was confirmed in patients having autopsy-proven AD with Braak stage III or IV but not in patients with non-AD dementias such as dementia with Lewy bodies, multiple system atrophy, and vascular dementia. LR11 messenger RNA is downregulated in lymphoblasts, and protein levels are reduced in cortical and hippocampal neurons from patients with LOAD but not patients with early-onset familial AD.4,6 This suggests that LR11 protein deficits might be detectable in plasma, but our attempts to measure plasma LR11 levels failed, and any relationship with more accessible blood messenger RNA levels needs to be explored. Together, this study provides preliminary evidence that the LR11 level may be a potential CSF biomarker for sporadic but not familial AD. In our sample, Aβ42 level was the best single CSF predictor of AD. Adding LR11 level to a discriminant function with Aβ42 level improved sensitivity and specificity (AUC changes from 0.789 to 0.865, P =.01), while adding T-tau or P-tau level did not. These are preliminary results and are without a validation sample. Because LR11 expression is sensitive to dietary omega-3 fatty acids,16 it is not surprising that LR11 level is not as closely connected to diagnosis as CSF Aβ42 level.

The stability of LR11 in CSF suggests that it may be used to monitor therapeutic effects of AD treatment. This would be particularly true in the case of drugs expected to work by modulating CNS LR11 expression such as the ω-3 fatty acid docosahexaenoic acid.16 Because of the limited non-AD dementia sample size herein, the potential of CSF LR11 level as a diagnostic marker for AD should be further investigated and combined with other biomarkers with larger sample sets, including MCI or preclinical cases. For example, it is possible that measuring the LR11 level alone in MCI or in combination with Aβ level would help to predict which patients with MCI are at highest risk for progression to AD.

Correspondence: Greg M. Cole, PhD, Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs (VA) Healthcare System, VA Medical Center, Research 151, Bldg 7, Room A101, 16111 Plummer St, North Hills, CA 91343 (gmcole@ucla.edu).

Accepted for Publication: June 8, 2008.

Author Contributions:Study concept and design: Ma, Frautschy, and Cole. Acquisition of data: Ma, Galasko, Ringman, Vinters, Pomakian, Ubeda, Rosario, and Cole. Analysis and interpretation of data: Ma, Galasko, Vinters, Edland, Pomakian, Rosario, Teter, and Cole. Drafting of the manuscript: Ma, Galasko, and Cole. Critical revision of the manuscript for important intellectual content: Ma, Galasko, Ringman, Vinters, Edland, Pomakian, Ubeda, Rosario, Teter, Frautschy, and Cole. Statistical analysis: Ma and Edland. Obtained funding: Cole. Administrative, technical, and material support: Ma, Galasko, Ringman, Vinters, Pomakian, Rosario, and Cole. Study supervision: Frautschy and Cole.

Financial Disclosure: None reported.

Funding/Support: This study was supported by grants AT3008 (Dr Cole), NIA AG13471 (Dr Cole), and P50 AG005131 (Dr Galasko) from the National Center for Complementary and Alternative Medicine, P01 AG16570 (Dr Cole; project 1, UCLA, ADRC), and NIR6-07-59659 from the Alzheimer's Association (Dr Ma). Dr Vinters was supported in part by the Daljit S. and Elaine Sarkaria Chair in Diagnostic Medicine, University of California, Los Angeles.

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PubMed
Blennow  KWallin  AAgren  HSpenger  CSiegfried  JVanmechelen  E Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol Chem Neuropathol 1995;26 (3) 231- 245
PubMed
Otto  MWiltfang  JTumani  H  et al.  Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurosci Lett 1997;225 (3) 210- 212
PubMed
Andreasen  NMinthon  LDavidsson  P  et al.  Evaluation of CSF-tau and CSF-Aβ42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 2001;58 (3) 373- 379
PubMed
Mollenhauer  BCepek  LBibl  M  et al.  Tau protein, Aβ42 and S-100B protein in cerebrospinal fluid of patients with dementia with Lewy bodies. Dement Geriatr Cogn Disord 2005;19 (2-3) 164- 170
PubMed
Hampe  WRiedel  IBLintzel  JBader  COFranke  ISchaller  HC Ectodomain shedding, translocation and synthesis of SorLA are stimulated by its ligand head activator. J Cell Sci 2000;113 (pt 24) 4475- 4485
PubMed
Ma  QLTeter  BUbeda  OJ  et al.  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 2007;27 (52) 14299- 14307
PubMed
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34 (7) 939- 944
PubMed
Folstein  MFFolstein  SEMcHugh  PR “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12 (3) 189- 198
PubMed
Mirra  SSHeyman  AMcKeel  D  et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), part II: standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 1991;41 (4) 479- 486
PubMed
Braak  HBraak  E Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 1991;82 (4) 239- 259
PubMed
Dickson  DWCrystal  HAMattiace  LA  et al.  Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol Aging 1992;13 (1) 179- 189
PubMed
Knopman  DSParisi  JESalviati  A  et al.  Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 2003;62 (11) 1087- 1095
PubMed
National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease, Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. Neurobiol Aging 1997;18 (4) ((suppl)) S1- S2
PubMed
Kosaka  KTsuchiya  KYoshimura  M Lewy body disease with and without dementia: a clinicopathological study of 35 cases. Clin Neuropathol 1988;7 (6) 299- 305
PubMed
Ma  QLHarris-White  MEUbeda  OJ  et al.  Evidence of Aβ- and transgene-dependent defects in ERK-CREB signaling in Alzheimer's models. J Neurochem 2007;103 (4) 1594- 1607
PubMed
Pepe  MSCai  TLongton  G Combining predictors for classification using the area under the receiver operating characteristic curve. Biometrics 2006;62 (1) 221- 229
PubMed
Sing  TSander  OBeerenwinkel  NLengauer  T ROCR: visualizing classifier performance in R. Bioinformatics 2005;21 (20) 3940- 3941
PubMed
Andersen  OMReiche  JSchmidt  V  et al.  Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 2005;102 (38) 13461- 13466
PubMed
Lannfelt  LBasun  HWahlund  LORowe  BAWagner  SL Decreased α-secretase-cleaved amyloid precursor protein as a diagnostic marker for Alzheimer's disease. Nat Med 1995;1 (8) 829- 832
PubMed
Van Nostrand  WEWagner  SLShankle  WR  et al.  Decreased levels of soluble amyloid β-protein precursor in cerebrospinal fluid of live Alzheimer disease patients. Proc Natl Acad Sci U S A 1992;89 (7) 2551- 2555
PubMed
Strittmatter  WJSaunders  AMSchmechel  D  et al.  Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 1993;90 (5) 1977- 1981
PubMed
Jacobsen  LMadsen  PMoestrup  SK  et al.  Molecular characterization of a novel human hybrid-type receptor that binds the α2-macroglobulin receptor–associated protein. J Biol Chem 1996;271 (49) 31379- 31383
PubMed
Yamazaki  HBujo  HKusunoki  J  et al.  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 1996;271 (40) 24761- 24768
PubMed
Montine  KSBassett  CNOu  JJMarkesbery  WRSwift  LLMontine  TJ Apolipoprotein E allelic influence on human cerebrospinal fluid apolipoproteins. J Lipid Res 1998;39 (12) 2443- 2451
PubMed
Marcusson  EGHorazdovsky  BFCereghino  JLGharakhanian  EEmr  SD The sorting receptor for yeast vacuolar carboxypeptidase Y is encoded by the VPS10 gene. Cell 1994;77 (4) 579- 586
PubMed
Jacobsen  LMadsen  PNielsen  MS  et al.  The sorLA cytoplasmic domain interacts with GGA1 and -2 and defines minimum requirements for GGA binding. FEBS Lett 2002;511 (1-3) 155- 158
PubMed
Spoelgen  Rvon Arnim  CAThomas  AV  et al.  Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and β-secretase β-site APP-cleaving enzyme. J Neurosci 2006;26 (2) 418- 428
PubMed
Cam  JABu  G Modulation of β-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family. Mol Neurodegener 2006;1e810.1186/1750-1326-1-8
Small  SAKent  KPierce  A  et al.  Model-guided microarray implicates the retromer complex in Alzheimer's disease. Ann Neurol 2005;58 (6) 909- 919
PubMed
Seaman  MN Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J Cell Biol 2004;165 (1) 111- 122
PubMed
He  XLi  FChang  WPTang  J GGA proteins mediate the recycling pathway of memapsin 2 (BACE). J Biol Chem 2005;280 (12) 11696- 11703
PubMed
Almkvist  OBasun  HWagner  SLRowe  BAWahlund  LOLannfelt  L Cerebrospinal fluid levels of α-secretase–cleaved soluble amyloid precursor protein mirror cognition in a Swedish family with Alzheimer disease and a gene mutation. Arch Neurol 1997;54 (5) 641- 644
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Sortilin-related receptor SorLA/LR11 (LR11) was secreted into culture medium from SH-SY5Y cells and into cerebrospinal fluid (CSF) in human brain. A, Western blot of approximately 250-kD LR11 band in SH-SY5Y cell lysates was slightly larger than the secreted LR11 band found in conditioned media. B, Secreted LR11 band in CSF in human brain is similarly slightly smaller than the LR11 membrane fraction band (lysis buffer extract).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Stability of sortilin-related receptor SorLA/LR11 (LR11) in cerebrospinal fluid (CSF) of patients with Alzheimer disease (AD). A, Western blot showed LR11, secretase-cleaved soluble β-amyloid precursor protein (sAPP), and apolipoprotein E (ApoE) band densities in CSF from a group of patients with AD having lumbar samples repeated after 6 months. The LR11, sAPP, and ApoE levels were highly stable between baseline and subsequent CSF draws. There were no significant differences between first and second CSF levels of LR11 (P = .81), α-secretase–cleaved APP (sAPPα) (P = .80), β-secretase–cleaved APP (sAPPβ) (P = .78), or ApoE (P = .65). Baseline and final CSF levels of LR11 (P < .001, r = 0.92 [B]), sAPPα (P < .001, r = 0.97 [C]), sAPPβ (P = .001, r = 0.72 [D]), and ApoE (P = .001, r = 0.78 [E]) significantly correlated with each other. OD indicates optical density.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

The sortilin-related receptor SorLA/LR11 (LR11) and secretase-cleaved soluble β-amyloid precursor protein (sAPP) levels in cerebrospinal fluid in patients with early Alzheimer disease (AD) were significantly decreased and correlated with the sAPP level but not the apolipoprotein (ApoE) level. A, Western blot showed that levels of LR11, α-secretase–cleaved APP (sAPPα), and β-secretase–cleaved (sAPPβ) significantly decreased in patients having early AD compared with control subjects (CTRLs), while the ApoE level did not show significant changes. β-Actin demonstrated the consistency with equal protein loading. B, Densitometric quantitation of LR11 from A confirmed a difference between patients with AD and CTRLs (P =.03). C, Densitometric quantitation of sAPPβ from A showed that sAPPβ was reduced in patients with AD compared with CTRLs (P =.02). D, Densitometric quantitation of ApoE from A showed that there was no difference in ApoE levels between patients with AD and CTRLs (P =.56). E, The LR11 level significantly correlated with sAPPβ level (P < .001, r =0.72). F, The LR11 level did not correlate with ApoE level (P =.46, r = 0.15). B-F, Open circle indicates CTRLs; solid circle, patients with AD; and OD, optical density.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Combining predictors for classification using the area under the receiver operating characteristic (ROC) curve. A, Univariate β42-amyloid (Aβ42) ROC curve with bivariate (LR11 and Aβ42) ROC curve overlain. Adding LR11 to the discriminant function with Aβ42 improved sensitivity and specificity (area under the ROC curve changes from 0.789 to 0.865, P =.01). B, Univariate Aβ42 ROC curve with bivariate (phosphorylated [P] tau and Aβ42) ROC curve overlain. Adding P-tau did not improve sensitivity and specificity (area under the ROC curve changes from 0.789 to 0.793).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

The sortilin-related receptor SorLA/LR11 (LR11) levels but not apolipoprotein E (ApoE) levels in postmortem cerebrospinal fluid samples from patients with autopsy-confirmed Alzheimer disease (AD) were significantly decreased. A, Western blot showed that the LR11 level was significantly decreased in patients with AD compared with healthy control subjects (CTRLs) or CTRLs with non-AD dementias (others); ApoE did not show significant differences. Roman numerals after AD indicate Braak stage. B, Densitometric quantification of LR11 from A confirmed a significant difference between patients with AD and healthy CTRLs or others (P < .05). C, Densitometric quantification of ApoE from A showed that there was no difference in ApoE levels between patients with AD and healthy CTRLs or others (P > .05). OD indicates optical density.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Clinical Characteristics of Cerebrospinal Fluid Sample Donors
Table Graphic Jump LocationTable 2. Description of Senile Plaque Densities and Neurofibrillary Tangles and Other Pathologic Characteristics of Cerebrospinal Fluid Samples From Patients With Autopsy-Based Disease and Healthy Control Subjects
Table Graphic Jump LocationTable 3. Summary Statistics for Comparison of LR11, β42-Amyloid, Total Tau, and P-tau Levels in the Expanded Sample

References

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PubMed
Rogaeva  EMeng  YLee  JH  et al.  The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 2007;39 (2) 168- 177
PubMed
Liu  FArias-Vásquez  ASleegers  K  et al.  A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population. Am J Hum Genet 2007;81 (1) 17- 31
PubMed
Scherzer  CROffe  KGearing  M  et al.  Loss of apolipoprotein E receptor LR11 in Alzheimer disease [published correction appears in Arch Neurol. 2007;64(4):557]. Arch Neurol 2004;61 (8) 1200- 1205
PubMed
Zhao  YCui  JGLukiw  WJ Reduction of sortilin-1 in Alzheimer hippocampus and in cytokine-stressed human brain cells. Neuroreport 2007;18 (11) 1187- 1191
PubMed
Dodson  SEGearing  MLippa  CFMontine  TJLevey  AILah  JJ LR11/SorLA expression is reduced in sporadic Alzheimer disease but not in familial Alzheimer disease. J Neuropathol Exp Neurol 2006;65 (9) 866- 872
PubMed
Sager  KLWuu  JLeurgans  SE  et al.  Neuronal LR11/sorLA expression is reduced in mild cognitive impairment. Ann Neurol 2007;62 (6) 640- 647
PubMed
Jendroska  KKashiwagi  MSassoon  JDaniel  SE Amyloid β-peptide and its relationship with dementia in Lewy body disease. J Neural Transm Suppl 1997;51137- 144
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Jendroska  KLees  AJPoewe  WDaniel  SE Amyloid β-peptide and the dementia of Parkinson's disease. Mov Disord 1996;11 (6) 647- 653
PubMed
Blennow  K Cerebrospinal fluid protein biomarkers for Alzheimer's disease. NeuroRx 2004;1 (2) 213- 225
PubMed
Blennow  KWallin  AAgren  HSpenger  CSiegfried  JVanmechelen  E Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol Chem Neuropathol 1995;26 (3) 231- 245
PubMed
Otto  MWiltfang  JTumani  H  et al.  Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurosci Lett 1997;225 (3) 210- 212
PubMed
Andreasen  NMinthon  LDavidsson  P  et al.  Evaluation of CSF-tau and CSF-Aβ42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 2001;58 (3) 373- 379
PubMed
Mollenhauer  BCepek  LBibl  M  et al.  Tau protein, Aβ42 and S-100B protein in cerebrospinal fluid of patients with dementia with Lewy bodies. Dement Geriatr Cogn Disord 2005;19 (2-3) 164- 170
PubMed
Hampe  WRiedel  IBLintzel  JBader  COFranke  ISchaller  HC Ectodomain shedding, translocation and synthesis of SorLA are stimulated by its ligand head activator. J Cell Sci 2000;113 (pt 24) 4475- 4485
PubMed
Ma  QLTeter  BUbeda  OJ  et al.  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 2007;27 (52) 14299- 14307
PubMed
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34 (7) 939- 944
PubMed
Folstein  MFFolstein  SEMcHugh  PR “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12 (3) 189- 198
PubMed
Mirra  SSHeyman  AMcKeel  D  et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), part II: standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 1991;41 (4) 479- 486
PubMed
Braak  HBraak  E Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 1991;82 (4) 239- 259
PubMed
Dickson  DWCrystal  HAMattiace  LA  et al.  Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol Aging 1992;13 (1) 179- 189
PubMed
Knopman  DSParisi  JESalviati  A  et al.  Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 2003;62 (11) 1087- 1095
PubMed
National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease, Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. Neurobiol Aging 1997;18 (4) ((suppl)) S1- S2
PubMed
Kosaka  KTsuchiya  KYoshimura  M Lewy body disease with and without dementia: a clinicopathological study of 35 cases. Clin Neuropathol 1988;7 (6) 299- 305
PubMed
Ma  QLHarris-White  MEUbeda  OJ  et al.  Evidence of Aβ- and transgene-dependent defects in ERK-CREB signaling in Alzheimer's models. J Neurochem 2007;103 (4) 1594- 1607
PubMed
Pepe  MSCai  TLongton  G Combining predictors for classification using the area under the receiver operating characteristic curve. Biometrics 2006;62 (1) 221- 229
PubMed
Sing  TSander  OBeerenwinkel  NLengauer  T ROCR: visualizing classifier performance in R. Bioinformatics 2005;21 (20) 3940- 3941
PubMed
Andersen  OMReiche  JSchmidt  V  et al.  Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 2005;102 (38) 13461- 13466
PubMed
Lannfelt  LBasun  HWahlund  LORowe  BAWagner  SL Decreased α-secretase-cleaved amyloid precursor protein as a diagnostic marker for Alzheimer's disease. Nat Med 1995;1 (8) 829- 832
PubMed
Van Nostrand  WEWagner  SLShankle  WR  et al.  Decreased levels of soluble amyloid β-protein precursor in cerebrospinal fluid of live Alzheimer disease patients. Proc Natl Acad Sci U S A 1992;89 (7) 2551- 2555
PubMed
Strittmatter  WJSaunders  AMSchmechel  D  et al.  Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 1993;90 (5) 1977- 1981
PubMed
Jacobsen  LMadsen  PMoestrup  SK  et al.  Molecular characterization of a novel human hybrid-type receptor that binds the α2-macroglobulin receptor–associated protein. J Biol Chem 1996;271 (49) 31379- 31383
PubMed
Yamazaki  HBujo  HKusunoki  J  et al.  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 1996;271 (40) 24761- 24768
PubMed
Montine  KSBassett  CNOu  JJMarkesbery  WRSwift  LLMontine  TJ Apolipoprotein E allelic influence on human cerebrospinal fluid apolipoproteins. J Lipid Res 1998;39 (12) 2443- 2451
PubMed
Marcusson  EGHorazdovsky  BFCereghino  JLGharakhanian  EEmr  SD The sorting receptor for yeast vacuolar carboxypeptidase Y is encoded by the VPS10 gene. Cell 1994;77 (4) 579- 586
PubMed
Jacobsen  LMadsen  PNielsen  MS  et al.  The sorLA cytoplasmic domain interacts with GGA1 and -2 and defines minimum requirements for GGA binding. FEBS Lett 2002;511 (1-3) 155- 158
PubMed
Spoelgen  Rvon Arnim  CAThomas  AV  et al.  Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and β-secretase β-site APP-cleaving enzyme. J Neurosci 2006;26 (2) 418- 428
PubMed
Cam  JABu  G Modulation of β-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family. Mol Neurodegener 2006;1e810.1186/1750-1326-1-8
Small  SAKent  KPierce  A  et al.  Model-guided microarray implicates the retromer complex in Alzheimer's disease. Ann Neurol 2005;58 (6) 909- 919
PubMed
Seaman  MN Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J Cell Biol 2004;165 (1) 111- 122
PubMed
He  XLi  FChang  WPTang  J GGA proteins mediate the recycling pathway of memapsin 2 (BACE). J Biol Chem 2005;280 (12) 11696- 11703
PubMed
Almkvist  OBasun  HWagner  SLRowe  BAWahlund  LOLannfelt  L Cerebrospinal fluid levels of α-secretase–cleaved soluble amyloid precursor protein mirror cognition in a Swedish family with Alzheimer disease and a gene mutation. Arch Neurol 1997;54 (5) 641- 644
PubMed

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