Presenilin 1 transgene addition to amyloid precursor protein overexpressing transgenic rats increases amyloid beta 42 levels and results in loss of memory retention

BMC Neurosci. 2016 Jul 7;17(1):46. doi: 10.1186/s12868-016-0281-8.

Abstract

Background: We previously reported the production of transgenic rats (APP21 line) that over-express human amyloid precursor protein (APP) containing Swedish and Indiana mutations. In order to generate a better model for Alzheimer's disease (AD), the APP21 rat line was used to generate double transgenic line that over-expressed Presenilin 1 (PS1) with L166P mutation in addition to APP transgene (APP + PS1 line).

Results: Thirty-two double transgenic founders were generated and the ultimate transgenic founder was selected based on PS1 transgene copy number and level of amyloid-beta (Aβ)42 peptide. The APP + PS1 double transgenic rats had 38 times more PS1 in brains compared to APP rats. Behavioral assessment using Barnes maze showed that APP + PS1 rats exhibited a larger learning and memory deficit than APP21 rats. Double transgenic rats also produced more Aβ42. Histological examination of the brains showed that the APP21 rat line displayed neurofibrillary tangles and in contrast, the APP + PS1 line showed chromatolysis in hippocampal neurons and neuronal loss in CA3 region of hippocampus.

Conclusions: Due to the separate segregation of APP and PS1 transgenes in APP + PS1 double transgenic rats, this transgenic line may be a valuable model for studying the effects of various levels of APP and PS1 transgenes on various aspects of brain pathologies associated with the AD phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Disease Models, Animal
  • Female
  • Humans
  • Maze Learning / physiology
  • Memory Disorders / metabolism*
  • Memory Disorders / pathology
  • Mutation
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Peptide Fragments / metabolism*
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism*
  • RNA, Messenger / metabolism
  • Rats, Inbred F344
  • Rats, Sprague-Dawley
  • Rats, Transgenic

Substances

  • APP protein, human
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • PSEN1 protein, human
  • Peptide Fragments
  • Presenilin-1
  • RNA, Messenger
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)