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

Kelly R. Bales, Tatyana Verina, David J. Cummins, Yansheng Du, Richard C. Dodel, Josep Saura, Cindy E. Fishman, Cynthia A. Delong, Pedro Piccardo, Valerie Petegnief, Bernardino Ghetti, Steven M. Paul

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Abstract

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 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 Aβ immunoreactivity in the hippocampus was also markedly reduced in an Apoe gene dose-dependent manner (Apoe(+/+) > Apoe(+/-) >> Apoe(-/-)), and no Aβ 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 Aβ1-40 and Aβ1-42 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 Aβ 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 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.

Original languageEnglish (US)
Pages (from-to)15233-15238
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number26
DOIs
StatePublished - Dec 21 1999

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    Bales, K. R., Verina, T., Cummins, D. J., Du, Y., Dodel, R. C., Saura, J., Fishman, C. E., Delong, C. A., Piccardo, P., Petegnief, V., Ghetti, B., & Paul, S. M. (1999). Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 96(26), 15233-15238. https://doi.org/10.1073/pnas.96.26.15233