Loss of apolipoprotein E receptor LR11 in Alzheimer disease.

Abstract

Genetic, epidemiologic, and biochemical evidence suggests that apolipoprotein E, low-density lipoprotein receptors, and lipid metabolism play important roles in sporadic Alzheimer disease (AD). To identify novel candidate genes associated with sporadic AD. 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. Emory University, Atlanta, Ga. Cell lines were used from 14 patients with AD and 9 normal human control subjects. 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). 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.