Published online before print November 30, 2007

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(American Journal of Pathology. 2007;171:2012-2020.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070403

Induction of Tau Pathology by Intracerebral Infusion of Amyloid-β-Containing Brain Extract and by Amyloid-β Deposition in APP x Tau Transgenic Mice

Tristan Bolmont^*, Florence Clavaguera, Melanie Meyer-Luehmann^*, Martin C. Herzig^*, Rebecca Radde^*, Matthias Staufenbiel, Jada Lewis, Mike Hutton, Markus Tolnay and Mathias Jucker^*

From the Department of Cellular Neurology,^* Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; the Department of Neuropathology, Institute of Pathology, University of Basel, Basel, Switzerland; Novartis Institutes for Biomedical Research, Basel, Switzerland; and the Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida

Alzheimer’s disease presents morphologically with senile plaques, primarily made of extracellular amyloid-β (Aβ) deposits, and neurofibrillary lesions, which consist of intracellular aggregates of hyperphosphorylated tau protein. To study the in vivo induction of tau pathology, dilute brain extracts from aged Aβ-depositing APP23 transgenic mice were intracerebrally infused in young B6/P301L tau transgenic mice. Six months after the infusion, tau pathology was induced in the injected hippocampus but also in brain regions well beyond the injection sites such as the entorhinal cortex and amygdala, areas with neuronal projection to the injection site. No or only modest tau induction was observed when brain extracts from aged nontransgenic control mice and aged tau-depositing B6/P301L transgenic mice were infused. To further study Aβ-induced tau lesions B6/P301L tau transgenic mice were crossed with APP23 mice. Although Aβ deposition in double-transgenic mice did not differ from single APP23 transgenic mice, double-transgenic mice revealed increased tau pathology compared to single B6/P301L tau transgenic mice predominately in areas with high Aβ plaque load. The present results suggest that both extract-derived Aβ species and deposited fibrillary Aβ can induce the formation of tau neurofibrillary pathology. The observation that infused Aβ can trigger the tau pathology in the absence of Aβ deposits provides an explanation for the discrepancy between the neuroanatomical location of Aβ deposits and the development and spreading of tau lesions in Alzheimer’s disease brain.

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