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

Lars N.G. Nilsson, Gary W. Arendash, Ralph E. Leighty, David A. Costa, Mark A. Low, Marcos F. Garcia, Jennifer R. Cracciolo, Amyn Rojiani, Xin Wu, Kelly R. Bales, Steven M. Paul, Huntington Potter

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67 Scopus citations

Abstract

Biochemical and genetic studies indicate that the inflammatory proteins, apolipoprotein E (ApoE) and α1-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 Aβ 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 Aβ peptide are unchanged by ApoE or ACT. These data suggest that the process or product of amyloid formation is more critical than monomeric Aβ for the neurological decline in AD, and that the risk factors ApoE and ACT participate primarily in disease processes downstream of APP processing.

Original languageEnglish (US)
Pages (from-to)1153-1167
Number of pages15
JournalNeurobiology of Aging
Volume25
Issue number9
DOIs
StatePublished - Oct 1 2004
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Amyloid deposition
  • Amyloid β-peptide
  • Apolipoprotein E
  • Inflammation
  • Learning
  • Memory
  • Transgenic mice
  • α-Antichymotrypsin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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    Nilsson, L. N. G., Arendash, G. W., Leighty, R. E., Costa, D. A., Low, M. A., Garcia, M. F., Cracciolo, J. R., Rojiani, A., Wu, X., Bales, K. R., Paul, S. M., & Potter, H. (2004). Cognitive impairment in PDAPP mice depends on ApoE and ACT-catalyzed amyloid formation. Neurobiology of Aging, 25(9), 1153-1167. https://doi.org/10.1016/j.neurobiolaging.2003.12.011