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

Lars N G Nilsson1, Gary W Arendash, Ralph E Leighty

  • 1Department of Biochemistry and Molecular Biology, Suncoast Gerontology Center, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA.

Neurobiology of Aging
|August 18, 2004
PubMed

Insights

Inflammatory proteins apolipoprotein E (ApoE) and alpha(1)-antichymotrypsin (ACT) accelerate Alzheimer's disease (AD) pathology. These proteins promote amyloid deposition and cognitive decline, highlighting their role downstream of amyloid precursor protein (APP) processing.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Genetics

Background:

  • Apolipoprotein E (ApoE) and alpha(1)-antichymotrypsin (ACT) are implicated in Alzheimer's disease (AD) pathogenesis.
  • Their specific roles in amyloid deposition and cognitive decline require further elucidation.

Purpose of the Study:

  • To investigate the independent and combined effects of murine ApoE and human ACT on amyloid deposition and cognitive impairment in a mouse model of AD.
  • To determine if ApoE and ACT influence amyloid precursor protein (APP) processing or downstream events.

Main Methods:

  • Utilized transgenic/knockout mouse models expressing PDAPP(V717F) mutation.
  • Administered ApoE and ACT to assess their impact on diffuse and fibrillar amyloid-beta (A beta) deposition.
  • Evaluated cognitive function and learning disabilities in aged mice.
  • Analyzed A beta peptide levels in young mice before amyloid formation.

Main Results:

  • Both ApoE and ACT, individually and synergistically, enhanced diffuse and fibrillar A beta deposition in PDAPP(V717F) mice.
  • Cognitive impairment severity strongly correlated with hippocampal amyloid burden, which was dependent on ApoE and ACT.
  • Mice lacking ApoE and ACT exhibited minimal amyloid deposition and learning deficits.
  • Steady-state levels of monomeric A beta peptide were unaffected by ApoE or ACT in young mice.

Conclusions:

  • ApoE and ACT play crucial roles in facilitating amyloid deposition and cognitive decline in Alzheimer's disease.
  • These risk factors appear to act downstream of APP processing, primarily influencing the process or product of amyloid formation rather than monomeric A beta levels.
  • Targeting ApoE and ACT may offer therapeutic strategies for mitigating AD progression.

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