Human APOE Isoform-Dependent Effects on Brain -Amyloid Levels in PDAPP Transgenic Mice

We have previously reported an important role for apolipoprotein E in the development of brain amyloid burden in the PDAPP transgenic mouse model of Alzheimer’s disease

K. R. Bales; F. Liu; S. Wu; S. Lin; D. Koger; C. DeLong; J. C. Hansen; P. M. Sullivan; S. M. Paul

2009

Scholarcy highlights

  • The ␧4 allele of the apolipoprotein E gene is a well established risk factor for late-onset Alzheimer’s disease, even in populations where the ␧4 allele is under-represented
  • Isoform-dependent differences in the level of apolipoprotein E protein in brain Using a sensitive ELISA, we determined the levels of apoE protein in plasma, CSF, and brain in PDAPP/ TRE2, 3, or 4 mice at various ages
  • The level of apoE in CSF was significantly greater in PDAPP/TRE2 mice when compared with PDAPP/TRE3 or PDAPP/TRE4 mice at either 3 or 18 months of age
  • The ␧4 allele of the APOE gene represents the most important genetic risk factor identified to date for the development of late onset AD, since ␧4 carriers have an increased risk for and an earlier age of disease onset
  • ␧4 carriers have a more rapid decline in memory function associated with aging
  • There was no significant difference in the level of APP mRNA regardless of APOE isoform in PDAPP/TRE mice as well as no significant difference in the level of APOE in either PDAPP/TRE or TRE only mice
  • An important role for apoE in determining brain A␤ burden in vivo has been established and numerous studies have documented an increase in brain A␤ burden in AD patients who are ␧4 carriers
  • Regardless of the exact pathophysiological mechanisms by which the ␧4 allele confers Alzheimer’s disease susceptibility, our results recapitulate in a transgenic mouse model an isoform-dependent increase in A␤/amyloid burden that appears to be tightly coupled to soluble apolipoprotein E levels

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