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Brain. 2014 Oct;137(Pt 10):2834-46. doi: 10.1093/brain/awu213. Epub 2014 Jul 31.

Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer's disease.

Author information

1
1 Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
2
2 Roche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
3
1 Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070 Basel, Switzerland fiona.grueninger@roche.com.

Abstract

The severity of tau pathology in Alzheimer's disease brain correlates closely with disease progression. Tau immunotherapy has therefore been proposed as a new therapeutic approach to Alzheimer's disease and encouraging results have been obtained by active or passive immunization of tau transgenic mice. This work investigates the mechanism by which immunotherapy can impact tau pathology. We demonstrate the development of Alzheimer's disease-like tau pathology in a triple transgenic mouse model of Alzheimer's disease and show that tau/pS422 is present in membrane microdomains on the neuronal cell surface. Chronic, peripheral administration of anti-tau/pS422 antibody reduces the accumulation of tau pathology. The unequivocal presence of anti-tau/pS422 antibody inside neurons and in lysosomes is demonstrated. We propose that anti-tau/pS422 antibody binds to membrane-associated tau/pS422 and that the antigen-antibody complexes are cleared intracellularly, thereby offering one explanation for how tau immunotherapy can ameliorate neuronal tau pathology.

KEYWORDS:

lipid rafts; tau immunotherapy; tau/pS422 antibody

PMID:
25085375
DOI:
10.1093/brain/awu213
[Indexed for MEDLINE]

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