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Intraneuronal APP, Not Free Aβ Peptides in 3xTg-AD Mice: Implications for Tau versus Aβ-Mediated Alzheimer Neurodegeneration

Matthew J. Winton, Edward B. Lee, Eveline Sun, Margaret M. Wong, Susan Leight, Bin Zhang, John Q. Trojanowski and Virginia M.-Y. Lee
Journal of Neuroscience 25 May 2011, 31 (21) 7691-7699; DOI: https://doi.org/10.1523/JNEUROSCI.6637-10.2011
Matthew J. Winton
1Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine and
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Edward B. Lee
1Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine and
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Eveline Sun
1Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine and
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Margaret M. Wong
1Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine and
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Susan Leight
1Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine and
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Bin Zhang
1Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine and
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John Q. Trojanowski
1Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine and
2Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
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Virginia M.-Y. Lee
1Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine and
2Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
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This article has been retracted. Please see:

  • Retraction: Winton et al., Intraneuronal APP, Not Free Aβ Peptides in 3xTg-AD Mice: Implications for Tau Versus Aβ-Mediated Alzheimer Neurodegeneration - February 25, 2015

Abstract

Alzheimer's disease (AD) is characterized by the accumulation of intraneuronal tau and extracellular amyloid-β (Aβ) peptide. A triple transgenic (Tg) mouse (3xTg-AD) was reported to develop Aβ plaques and tau inclusions as well as remarkable accumulations of intracellular Aβ that were suggested to be the initiators of AD pathogenesis. However, it was unclear whether the anti-Aβ antibodies were able to distinguish Aβ peptide from the same Aβ epitopes within the amyloid precursor protein (APP). To further elucidate the identity of the immunoreactive intraneuronal material in 3xTg-AD mice, we conducted immunohistochemical, biochemical, and ultrastructural studies using a well characterized panel of antibodies that distinguish Aβ within APP from cleaved Aβ peptides. We found that the intraneuronal material shared epitopes with full-length APP but not free Aβ. To demonstrate unequivocally that this intraneuronal material was not free Aβ peptide, we generated 3xTg-AD mice deficient for β-secretase (BACE), the protease required for Aβ generation from APP. In the absence of Aβ production, robust intraneuronal APP immunostaining was detected in the 3xTg-AD/BACE−/− mice. Finally, we found that the formation of tau lesions was not different between 3xTg-AD versus 3xTg-AD/BACE−/− mice, thereby demonstrating that tau pathology forms independently from Aβ peptide generation in this mouse model. Although we cannot corroborate the presence of intraneuronal Aβ peptide in 3xTg-AD mice, our findings warrant further study as to the role of aberrant APP accumulation in this unique model of AD.

Footnotes

  • Correspondence should be addressed to Virginia M.-Y. Lee, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Maloney Building, Third Floor, Hospital of the University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-4283; vmylee{at}upenn.edu
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The Journal of Neuroscience: 31 (21)
Journal of Neuroscience
Vol. 31, Issue 21
25 May 2011
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Intraneuronal APP, Not Free Aβ Peptides in 3xTg-AD Mice: Implications for Tau versus Aβ-Mediated Alzheimer Neurodegeneration
Matthew J. Winton, Edward B. Lee, Eveline Sun, Margaret M. Wong, Susan Leight, Bin Zhang, John Q. Trojanowski, Virginia M.-Y. Lee
Journal of Neuroscience 25 May 2011, 31 (21) 7691-7699; DOI: 10.1523/JNEUROSCI.6637-10.2011

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Intraneuronal APP, Not Free Aβ Peptides in 3xTg-AD Mice: Implications for Tau versus Aβ-Mediated Alzheimer Neurodegeneration
Matthew J. Winton, Edward B. Lee, Eveline Sun, Margaret M. Wong, Susan Leight, Bin Zhang, John Q. Trojanowski, Virginia M.-Y. Lee
Journal of Neuroscience 25 May 2011, 31 (21) 7691-7699; DOI: 10.1523/JNEUROSCI.6637-10.2011
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