Abstract
Accumulation of β-amyloid (Aβ) in the brain is essential to Alzheimer’s disease (AD) pathogenesis. Carriers of the apolipoprotein E (APOE) ε4 allele demonstrate greatly increased AD risk and enhanced brain Aβ deposition. In contrast, APOE ε2 allele carries show reduced AD risk, later age of disease onset, and lesser Aβ accumulation. However, it remains elusive whether the apoE2 isoform exerts truly protective effect against Aβ pathology or apoE2 plays deleterious role albeit less pronounced than the apoE4 isoform. Here, we characterized APPSW/PS1dE9/APOE ε2-TR (APP/E2) and APPSW/PS1dE9/APOE ε4-TR (APP/E4) mice, with targeted replacement (TR) of the murine Apoe for human ε2 or ε4 alleles, and used these models to investigate effects of pharmacological inhibition of the apoE/Aβ interaction on Aβ deposition and neuritic degeneration. APP/E2 and APP/E4 mice replicate differential effect of human apoE isoforms on Aβ pathology with APP/E4 mice showing a several-fold greater load of Aβ plaques, insoluble brain Aβ levels, Aβ oligomers, and density of neuritic plaques than APP/E2 mice. Furthermore, APP/E4 mice, but not APP/E2 mice, exhibit memory impairment on object recognition and radial arm maze tests. Between the age of 6 and 10 months APP/E2 and APP/E4 mice received treatment with Aβ12-28P, a non-toxic, synthetic peptide homologous to the apoE binding motif within the Aβ sequence, which competitively blocks the apoE/Aβ interaction. In both lines, the treatment significantly reduced brain Aβ accumulation, co-accumulation of apoE within Aβ plaques, and neuritic degeneration, and prevented memory deficit in APP/E4 mice. These results indicate that both apoE2 and apoE4 isoforms contribute to Aβ deposition and future therapies targeting the apoE/Aβ interaction could produce favorable outcome in APOE ε2 and ε4 allele carriers.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0075-0) contains supplementary material, which is available to authorized users.
Highlights
Alzheimer’s disease (AD) is a familial and sporadic neurodegenerative disease
Human apolipoprotein E (APOE) alleles targeted to APPSW/PS1dE9 mice reproduce their differential effect on the magnitude of Aβ plaque load [13] but do not delay onset of Aβ deposition compared to APPSW/PS1dE9 mice expressing native murine apoE [14]
We demonstrated here that APOE ε2 and APOE ε4 targeted replacement in APPSW/PS1dE9 AD Tg model mice reproduces the differential effect of encoded by these alleles apoE isoforms on various aspects of Aβ pathology and associated neurodegeneration
Summary
Alzheimer’s disease (AD) is a familial and sporadic neurodegenerative disease. Its neuropathological hallmarks include parenchymal plaques and vascular deposits of β-amyloid (Aβ), intraneuronal paired helical filaments composed of hyperphosphorylated tau and ubiquitin, widespread loss of synapses and neurons, and the appearance of reactive astrocytes and microglia. Human APOE alleles targeted to APPSW/PS1dE9 mice reproduce their differential effect on the magnitude of Aβ plaque load [13] but do not delay onset of Aβ deposition compared to APPSW/PS1dE9 mice expressing native murine apoE [14]. Since these APPSW/PS1dE9/APOE ε2-TR and APPSW/PS1dE9/APOE ε4-TR lines (hereafter designated as APP/E2 and APP/E4; respectively) are novel AD Tg animal models, their behavioral and biochemical characterization was undertaken as a part of this study. This study evaluated the prospects for disrupting the apoE/Aβ interaction in human population diversified by the occurrence of various APOE alleles
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