Apolipoprotein E is essential for amyloid deposition in the APPV717F transgenic mouse model of Alzheimer's disease

We quantified the amount of amyloid beta-peptide (A beta) 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 beta immunoreactivity in the hippocampus was also markedly reduced in an Apoe gene dose-dependent manner (Apoe(+/+) > Apoe(+/-) much greater than Apoe(-/-)), and no A beta 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 A beta(1-40) and A beta(1-42) 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 beta immunoreactive deposits and in virtually all thioflavine-S-fluorescent amyloid deposits. Because the absence of apoE alters neither the transcription or translation of the APP(V717F) transgene nor its processing to A beta peptide(s), we postulate that apoE promotes both the deposition and fibrillization of A beta, ultimately affecting clearance of protease-resistant A beta/apoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathological hallmarks of Alzheimer's disease.