Loss of Apolipoprotein E Receptor LR11 in Alzheimer Disease

Arch Neurol. 2004 Aug;61(8):1200-5. doi: 10.1001/archneur.61.8.1200.

Abstract

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.

Design: 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.

Setting: Emory University, Atlanta, Ga.

Subjects: 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Brain / metabolism
  • Cell Line, Transformed
  • Female
  • Humans
  • LDL-Receptor Related Proteins
  • Low Density Lipoprotein Receptor-Related Protein-1 / biosynthesis
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism*
  • Lymphocytes / metabolism
  • Male
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / metabolism*
  • Membrane Transport Proteins / biosynthesis
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Middle Aged
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / metabolism*
  • Oligonucleotide Array Sequence Analysis / methods
  • Receptors, LDL / biosynthesis
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*

Substances

  • Adaptor Proteins, Vesicular Transport
  • LDL-Receptor Related Proteins
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Receptors, LDL
  • SORL1 protein, human
  • sortilin