Cognitive impairment in PDAPP mice depends on ApoE and ACT-catalyzed amyloid formation

Neurobiol Aging. 2004 Oct;25(9):1153-67. doi: 10.1016/j.neurobiolaging.2003.12.011.

Abstract

Biochemical and genetic studies indicate that the inflammatory proteins, apolipoprotein E (ApoE) and alpha(1)-antichymotrypsin (ACT) are important in the pathogenesis of Alzheimer's disease (AD). Using several lines of multiply transgenic/knockout mice we show here that murine ApoE and human ACT separately and synergistically facilitate both diffuse A beta immunoreactive and fibrillar amyloid deposition and thus also promote cognitive impairment in aged PDAPP(V717F) mice. The degree of cognitive impairment is highly correlated with the ApoE- and ACT-dependent hippocampal amyloid burden, with PDAPP mice lacking ApoE and ACT having little amyloid and little learning disability. A analysis of young mice before the onset of amyloid formation shows that steady-state levels of monomeric A beta peptide are unchanged by ApoE or ACT. These data suggest that the process or product of amyloid formation is more critical than monomeric A beta for the neurological decline in AD, and that the risk factors ApoE and ACT participate primarily in disease processes downstream of APP processing.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging / genetics
  • Aging / metabolism
  • Aging / pathology
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism*
  • Brain / metabolism
  • Brain / pathology
  • Brain / physiopathology*
  • Cognition Disorders / genetics
  • Cognition Disorders / metabolism
  • Cognition Disorders / physiopathology*
  • Disease Models, Animal
  • Encephalitis / genetics
  • Encephalitis / metabolism
  • Encephalitis / physiopathology
  • Female
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Learning Disabilities / genetics
  • Learning Disabilities / metabolism
  • Learning Disabilities / physiopathology
  • Male
  • Maze Learning / physiology
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Plaque, Amyloid / genetics
  • Plaque, Amyloid / metabolism
  • alpha 1-Antichymotrypsin / genetics
  • alpha 1-Antichymotrypsin / metabolism*

Substances

  • Amyloid beta-Peptides
  • Apolipoproteins E
  • alpha 1-Antichymotrypsin