Apolipoprotein E is essential for amyloid deposition in the APP V717F transgenic mouse model of Alzheimer's disease

We quantified the amount of amyloid β-peptide (Aβ) 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 ofAPP V717F+/− Apoe −/− TG mice as old as 22 mo of age, whereas age-matchedAPP V717F +/− Apoe +/− andApoe +/+ TG mice display abundant amyloid deposition. The amount of Aβ immunoreactivity in the hippocampus was also markedly reduced in anApoe gene dose-dependent manner (Apoe +/+ >Apoe +/− ≫Apoe −/− ), and no Aβ immunoreactivity was detected in the cerebral cortex ofAPP V717F+/− Apoe −/− TG mice at any of the time points examined. The absence of apolipoprotein E protein (apoE) dramatically reduced the amount of both Aβ1–40 and Aβ1–42 immunoreactive deposits as well as the resulting astrogliosis and microgliosis normally observed inAPP V717F TG mice. ApoE immunoreactivity was detected in a subset of Aβ immunoreactive deposits and in virtually all thioflavine-S-fluorescent amyloid deposits. Because the absence of apoE alters neither the transcription or translation of theAPP V717F transgene nor its processing to Aβ peptide(s), we postulate that apoE promotes both the deposition and fibrillization of Aβ, ultimately affecting clearance of protease-resistant Aβ/apoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathological hallmarks of Alzheimer's disease.