title: Intraneuronal APP, not free Aβ peptides in 3xTg-AD mice: implications for tau versus Aβ-mediated Alzheimer neurodegeneration.
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.
authors: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors: Matthew J
authors: MJ
authors: Winton
authors: Edward B
authors: EB
authors: Lee
authors: Eveline
authors: E
authors: Sun
authors: Margaret M
authors: MM
authors: Wong
authors: Susan
authors: S
authors: Leight
authors: Bin
authors: B
authors: Zhang
authors: John Q
authors: JQ
authors: Trojanowski
authors: Virginia M-Y
authors: VM
authors: Lee
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