Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice.
Alzheimer's disease presents morphologically with senile plaques, primarily made of extracellular amyloid-beta (A beta) 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 A beta-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 A beta-induced tau lesions B6/P301L tau transgenic mice were crossed with APP23 mice. Although A beta 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 A beta plaque load. The present results suggest that both extract-derived A beta species and deposited fibrillary A beta can induce the formation of tau neurofibrillary pathology. The observation that infused A beta can trigger the tau pathology in the absence of A beta deposits provides an explanation for the discrepancy between the neuroanatomical location of A beta deposits and the development and spreading of tau lesions in Alzheimer's disease brain.
Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller Str.27, D-72076 Tübingen, Germany.
Tristan
T
Bolmont
Florence
F
Clavaguera
Melanie
M
Meyer-Luehmann
Martin C
MC
Herzig
Rebecca
R
Radde
Matthias
M
Staufenbiel
Jada
J
Lewis
Mike
M
Hutton
Markus
M
Tolnay
Mathias
M
Jucker
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001923:Brain Chemistry; D002457:Cell Extracts / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D024801:Tauopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002457:Cell Extracts; D016875:tau Proteins