Publikationsdatum:
2014-02-08
Beschreibung:
Intraneuronal accumulation of β-amyloid (Aβ) 42 is one of the earliest pathological events in humans and in animal models of Alzheimer's disease (AD). Apolipoprotein E 4 (APOE4) is the major identified genetic risk factor for late-onset AD, with Aβ deposition beginning earlier in apoE4-positive subjects. To directly determine the effects of APOE genotype on intraneuronal accumulation of Aβ 1–42 at the onset of AD pathogenesis, we introduced lentiviral Aβ 1–42 into the cortex of APOE targeted replacement (TR) mice at the age of 8–9 months. We demonstrated a significant isoform-dependent effect of human APOE, with dramatically enhanced intracellular Aβ 1–42 deposits in the cerebral cortex of APOE4-TR mice 2 weeks after injection. Double-immunofluorescent staining showed that intracellular accumulation of lentiviral Aβ 1–42 was mainly present in neurons, localized to late endosomes/lysosomes. This intraneuronal accumulation of Aβ 1–42 correlated with increased tau phosphorylation and cell death in the ipsilateral cortex around the injection site. Aβ 1–42 was also observed in microglia, but not in astrocytes. Quantitative analysis revealed more neurons with Aβ 1–42 while less microglia with Aβ 1–42 nearest to the injection site of Aβ 1–42 lentivirus in APOE4-TR mice. Finally, apoE was present in neurons of the ipsilateral cortex of APOE-TR mice at 2 weeks after lentivirus injection, in addition to astrocytes and microglia in both the ipsilateral and contralateral cerebral cortex. Taken together, these results demonstrate that apoE4 tips the balance of the glial and neuronal Aβ toward the intraneuronal accumulation of Aβ.
Print ISSN:
0964-6906
Digitale ISSN:
1460-2083
Thema:
Biologie
,
Medizin
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