BRI2 (ITM2b) inhibits Abeta deposition in vivo

J Neurosci. 2008 Jun 4;28(23):6030-6. doi: 10.1523/JNEUROSCI.0891-08.2008.

Abstract

Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid beta precursor protein (APP) genes support the hypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer's disease (AD) is associated with neurodegeneration. We have used somatic brain transgenic technology to express the BRI2 and BRI2-Abeta1-40 transgenes in APP mouse models. Expression of BRI2-Abeta1-40 mimics the suppressive effect previously observed using conventional transgenic methods, further validating the somatic brain transgenic methodology. Unexpectedly, we also find that expression of wild-type human BRI2 reduces cerebral Abeta deposition in an AD mouse model. Additional data indicate that the 23 aa peptide, Bri23, released from BRI2 by normal processing, is present in human CSF, inhibits Abeta aggregation in vitro and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of Abeta deposition in vivo.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amyloid / genetics
  • Amyloid / physiology*
  • Amyloid beta-Peptides / administration & dosage
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / administration & dosage
  • Amyloid beta-Protein Precursor / antagonists & inhibitors*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Chickens
  • Cricetinae
  • Dependovirus / genetics
  • Female
  • Gene Transfer Techniques
  • Humans
  • Male
  • Membrane Glycoproteins
  • Membrane Proteins
  • Mice
  • Mice, Transgenic
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Phenotype

Substances

  • Adaptor Proteins, Signal Transducing
  • Amyloid
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • ITM2B protein, human
  • Membrane Glycoproteins
  • Membrane Proteins
  • Peptide Fragments
  • amyloid beta-protein (1-40)