We quantified the amount of amyloid -peptide (A) immunoreactivity as well as amyloid deposits in a large cohort of transgenic mice overexpressing the V717F human amyloid precursor protein (APP V717F؉/؊ TG mice) with no, one, or two mouse apolipoprotein E (Apoe) alleles at various ages. Remarkably, no amyloid deposits were found in any brain region of APP V717F؉/؊ Apoe ؊/؊ TG mice as old as 22 mo of age, whereas age-matched APP V717F ؉/؊ Apoe ؉/؊ and Apoe ؉/؉ TG mice display abundant amyloid deposition. The amount of A immunoreactivity in the hippocampus was also markedly reduced in an Apoe gene dose-dependent manner (Apoe ؉/؉ > Apoe ؉/؊ Ͼ Ͼ Apoe ؊/؊ ), and no A immunoreactivity was detected in the cerebral cortex of APP V717F؉/؊ Apoe ؊/؊ TG mice at any of the time points examined. The absence of apolipoprotein E protein (apoE) dramatically reduced the amount of both A1-40 and A1-42 immunoreactive deposits as well as the resulting astrogliosis and microgliosis normally observed in APP V717F TG mice. ApoE immunoreactivity was detected in a subset of A immunoreactive deposits and in virtually all thioflavine-Sfluorescent amyloid deposits. Because the absence of apoE alters neither the transcription or translation of the APP V717F transgene nor its processing to A peptide(s), we postulate that apoE promotes both the deposition and fibrillization of A, ultimately affecting clearance of protease-resistant A/apoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathological hallmarks of Alzheimer's disease.
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