Journal of Molecular Neuroscience

, Volume 23, Issue 3, pp 255–262 | Cite as

Apolipoprotein E dose-dependent modulation of β-amyloid deposition in a transgenic mouse model of Alzheimer’s disease

Original Article

Abstract

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 β-amyloid (Aβ) and that amyloid plaques can modify this equilibrium. Trafficking of soluble central nervous system (CNS) Aβ is a very dynamic system that almost certainly is modulated by Aβ-binding proteins. Altered trafficking of the Aβ 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 Aβ trafficking, we developed PDAPP transgenic mice that express different levels of human apoE3. Analysis of the soluble CNS pools of Aβ in young mice showed an apoE3 dose-dependent decrease in Aβ levels (E3−/−>E3−/−>E3+/+). In addition to the dose-dependent effects on soluble Aβ, by 15 mo of age there were highly significant differences in the amount of deposited Aβ between the genotypes (E3−/−>E3−/−>E3+/+). These data indicate that apoE3 provides a dose-dependent protective effect against Aβ deposition. This study suggests that increasing human apoE levels in brain might be a possible therapeutic target for preventing AD.

Index Entries

Apolipoprotein E Alzheimer’s disease amyloid transgenic cerebralspinal fluid 

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Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  1. 1.Neuroscience Discovery ResearchEli Lilly and Co., Lilly Research LaboratoriesIndianapolis

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