Tau-targeting passive immunization modulates aspects of pathology in tau transgenic mice
Article first published online: 1 AUG 2014
© 2014 International Society for Neurochemistry
Journal of Neurochemistry
Volume 132, Issue 1, pages 135–145, January 2015
How to Cite
J. Neurochem. (2015) 132, 135–145.
- Issue published online: 17 DEC 2014
- Article first published online: 1 AUG 2014
- Accepted manuscript online: 12 JUL 2014 06:19AM EST
- Manuscript Accepted: 30 JUN 2014
- Manuscript Revised: 29 JUN 2014
- Manuscript Received: 28 MAY 2014
- Neotope Biosciences
- National Health & Medical Research Council
- Australian Research Council
- Alzheimer Association
- Jane Mason & Harold Stannett Williams Memorial Foundation
- Alzheimer's disease;
- passive immunization;
Immunization is increasingly recognized as a suitable therapeutic avenue for the treatment of neurological diseases such as Alzheimer's disease and other tauopathies. Tau is a key molecular player in these conditions and therefore represents an attractive target for passive immunization approaches. We performed such an approach in two independent tau transgenic mouse models of tauopathy, K369I tau transgenic K3 and P301L tau transgenic pR5 mice. The antibodies we used were either specific for full-length tau or tau phosphorylated at serine 404 (pS404), a residue that forms part of the paired helical filament (PHF)-1 phosphoepitope that characterizes tau neurofibrillary tangles in tauopathies. Although both pS404 antibodies had a similar affinity, they differed in isotype, and only passive immunization with the IgG2a/κ pS404-specific antibody resulted in a lower tangle burden and reduced phosphorylation of tau at the PHF1 epitope in K3 mice. In pR5 mice, the same antibody led to a reduced phosphorylation of the pS422 and PHF1 epitopes of tau. In addition, histological sections of the hippocampal dentate gyrus of the immunized pR5 mice displayed reduced pS422 staining intensities. These results show that passive immunization targeting tau can modulate aspects of tau pathology in tau transgenic mouse models, in an antibody isotype-specific manner.
We show that passive immunization targeting the pathological phosphorylation site pS404 on human tau with a monoclonal IgG2a/κ, but not a IgG1/κ antibody, reduced hyperphosphorylation of tau and tangle burden in two independent mouse models of tau pathology. This shows that both specificity and isotype of phospho-tau (p-tau)-specific antibodies are important for therapeutically ameliorating tau pathology.