Loss of apolipoprotein E receptor LR11 in Alzheimer disease.
BACKGROUND
Genetic, epidemiologic, and biochemical evidence suggests that apolipoprotein E, low-density lipoprotein receptors, and lipid metabolism play important roles in sporadic Alzheimer disease (AD).


OBJECTIVE
To identify novel candidate genes associated with sporadic AD.


METHODS
We performed an unbiased microarray screen for genes differentially expressed in lymphoblasts of patients with sporadic AD and prioritized 1 gene product for further characterization in AD brain.


METHODS
Emory University, Atlanta, Ga.


METHODS
Cell lines were used from 14 patients with AD and 9 normal human control subjects.


RESULTS
Six genes were differentially expressed in lymphoblasts of 2 independent groups of patients with probable AD and autopsy-proven AD. We hypothesized that 1 of the genes, termed low-density lipoprotein receptor relative with 11 binding repeats (LR11) (reduced 1.8- and 2.5-fold in AD lymphoblasts vs controls), might be associated with sporadic AD on the basis of its function as neuronal apolipoprotein E receptor. We found dramatic and consistent loss of immunocytochemical staining for LR11 in histologically normal-appearing neurons in AD brains. This reduction of LR11 protein was confirmed by quantitative Western blotting (P =.01).


CONCLUSIONS
There is loss of the microarray-derived candidate, LR11, in neurons of AD brains. This study shows that microarray analysis of widely available lymphoblasts derived from patients with AD holds promise as a primary screen for candidate genes associated with AD.
Department of Neurology, Emory University, Atlanta, Ga, USA.
Clemens R
CR
Scherzer
Katrin
K
Offe
Marla
M
Gearing
Howard D
HD
Rees
Guofu
G
Fang
Craig J
CJ
Heilman
Chica
C
Schaller
Hideaki
H
Bujo
Allan I
AI
Levey
James J
JJ
Lah
D033942:Adaptor Proteins, Vesicular Transport; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002461:Cell Line, Transformed; D005260:Female; D006801:Humans; D026502:LDL-Receptor Related Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011973:Receptors, LDL / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D026502:LDL-Receptor Related Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011973:Receptors, LDL; D000099183:Sortilin; C102582:SORL1 protein, human