Reduction of SorLA/LR11, a sorting protein limiting beta-amyloid production, in Alzheimer disease cerebrospinal fluid.
BACKGROUND
The sortilin-related receptor SorLA/LR11 (LR11) is a transmembrane neuronal sorting protein that reduces beta-amyloid precursor protein trafficking to secretases, notably BACE1 that generates beta-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 beta-amyloid precursor protein) LR11 is cleaved near the membrane to release a large N-terminal fragment that is secreted to media from cultured cells.


METHODS
Case-control study.


METHODS
Academic research.


METHODS
Patients with AD and control subjects.


METHODS
We evaluated CSF LR11, beta-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 beta-amyloid 42 and LR11 levels improved diagnostic specificity for AD. Reduced LR11 levels are significantly correlated with soluble beta-amyloid precursor protein but not apolipoprotein E levels.


CONCLUSIONS
Reduced LR11 levels in CSF of patients with AD may have potential as a diagnostic biomarker for patients with LR11 deficits that promote beta-amyloid production or as an index of therapeutic response in late-onset AD.
Department of Medicine, University of California, Los Angeles, California, USA.
Qiu-Lan
QL
Ma
Douglas R
DR
Galasko
John M
JM
Ringman
Harry V
HV
Vinters
Steven D
SD
Edland
Justine
J
Pomakian
Oliver J
OJ
Ubeda
Emily R
ER
Rosario
Bruce
B
Teter
Sally A
SA
Frautschy
Greg M
GM
Cole
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid; D001057:Apolipoproteins E / Q000134:cerebrospinal fluid; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002460:Cell Line; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000134:cerebrospinal fluid* / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000134:cerebrospinal fluid* / Q000235:genetics*; D016874:Neurofibrillary Tangles / Q000473:pathology; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D058225:Plaque, Amyloid / Q000473:pathology; D011237:Predictive Value of Tests; D012016:Reference Values
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D010446:Peptide Fragments; C102582:SORL1 protein, human; C075222:amyloid beta-protein (1-42)