Expression of the Alzheimer's Disease Mutations AβPP695sw and PSEN1M146I in Double-Transgenic Göttingen Minipigs

J Alzheimers Dis. 2016 Jul 14;53(4):1617-30. doi: 10.3233/JAD-160408.

Abstract

Mutations in the amyloid-β protein precursor gene (AβPP), the presenilin 1 gene (PSEN1) or the presenilin 2 gene (PSEN2) that increase production of the AβPP-derived peptide Aβ42 cause early-onset Alzheimer's disease. Rodent models of the disease show that further increase in Aβ42 production and earlier brain pathology can be obtained by coexpressing AβPP and PSEN1 mutations. To generate such elevated Aβ42 level in a large animal model, we produced Göttingen minipigs carrying in their genome one copy of a human PSEN1 cDNA with the Met146Ile (PSEN1M146I) mutation and three copies of a human AβPP695 cDNA with the Lys670Asn/Met671Leu (AβPPsw) double-mutation. Both transgenes were expressed in fibroblasts and in the brain, and their respective proteins were processed normally. Immunohistochemical staining with Aβ42-specific antibodies detected intraneuronal accumulation of Aβ42 in brains from a 10- and an 18-month-old pig. Such accumulation may represent an early event in the pathogenesis of Alzheimer's disease.

Keywords: Alzheimer’s disease; amyloid; porcine model; presenilin; transgenic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics*
  • Animals
  • Animals, Genetically Modified
  • Brain / metabolism
  • Brain / pathology
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Fibroblasts / metabolism
  • Gene Expression Regulation / genetics*
  • Male
  • Mutation / genetics*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Presenilin-1 / genetics*
  • Swine
  • Swine, Miniature
  • Transfection

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Peptide Fragments
  • Presenilin-1
  • amyloid beta-protein (1-42)
  • Amyloid Precursor Protein Secretases