Apolipoprotein E dose-dependent modulation of beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease.
Susceptibility to the development of Alzheimer's disease (AD) is increased for individuals harboring one or more apolipoprotein E4 (apoE4) alleles. Even though several isoform-specific effects of apoE have been identified, the relationship between biochemical function and risk factor assessment remains unknown. Our previous studies have demonstrated that there is an equilibrium between cerebral spinal fluid (CSF) and plasma beta-amyloid (Abeta) and that amyloid plaques can modify this equilibrium. Trafficking of soluble central nervous system (CNS) Abeta is a very dynamic system that almost certainly is modulated by Abeta-binding proteins. Altered trafficking of the Abeta peptide might have a dramatic consequence as to whether the peptide is metabolized or begins to deposit within the brain. To gain a better understanding of the molecular mechanisms by which apoE influences AD pathogenesis and/or Abeta trafficking, we developed PDAPP transgenic mice that express different levels of human apoE3. Analysis of the soluble CNS pools of Abeta in young mice showed an apoE3 dose-dependent decrease in Abeta levels (E3-/- > E3-/- > E3+/+). In addition to the dose-dependent effects on soluble Abeta, by 15 mo of age there were highly significant differences in the amount of deposited Abeta between the genotypes (E3-/- > E3-/- > E3+/+). These data indicate that apoE3 provides a dose-dependent protective effect against Abeta deposition. This study suggests that increasing human apoE levels in brain might be a possible therapeutic target for preventing AD.
DeMattos
Ronald B
RB
Eli Lilly and Co., Lilly Research Laboratories, Neuroscience Discovery Research Indianapolis, IN 46285, USA. demattos_ronald_bradley@lilly.com
D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E