This paper adds further credence to the notion that vaccine/immune therapy directed at pathological tau species in AD and other tauopathies may abrogate disease progression in these disorders.

View all comments by John Trojanowski

I understand here that antibodies enter the brain, but not necessarily the neurons, and that immunotherapy here works for extracellular tangles, reducing part of the late-event burden. But does the immunotherapy work on the intracellular pathological factors?

View all comments by Andre Delacourte

Andre Delacourte raises a good question about extracellular versus intracellular clearance. It is certainly possible that extracellular tangles may be cleared, but we show that intraneuronal tau aggregates are targeted as well. The paper discusses this in more detail but briefly, intracarotid injection of FITC-labeled IgG purified from a high-titer mouse led to intraneuronal FITC labeling in the brains of P301L mice. When these brain sections were incubated with PHF1 or MC1, these second antibodies colocalized with the FITC-labeled IgG (see Figure 9). Figures 7-9 demonstrate perinuclear staining that is highly localized. The distribution of neuronal staining clearly demarcated the neurons and accumulated predominantly in the apical part of the cell soma and probably also partially in the plasma membrane. Carotid injection in another set of P301L mice with FITC-labeled control IgG resulted in some non-specific fluorescence within the brain and did not colocalize with PHF1 or MC1 staining. Furthermore, the identical approach with the same FITC-labeled antibodies in wild-type mice...  Read more

Andre Delacourte raises a good question about extracellular versus intracellular clearance. It is certainly possible that extracellular tangles may be cleared, but we show that intraneuronal tau aggregates are targeted as well. The paper discusses this in more detail but briefly, intracarotid injection of FITC-labeled IgG purified from a high-titer mouse led to intraneuronal FITC labeling in the brains of P301L mice. When these brain sections were incubated with PHF1 or MC1, these second antibodies colocalized with the FITC-labeled IgG (see Figure 9). Figures 7-9 demonstrate perinuclear staining that is highly localized. The distribution of neuronal staining clearly demarcated the neurons and accumulated predominantly in the apical part of the cell soma and probably also partially in the plasma membrane. Carotid injection in another set of P301L mice with FITC-labeled control IgG resulted in some non-specific fluorescence within the brain and did not colocalize with PHF1 or MC1 staining. Furthermore, the identical approach with the same FITC-labeled antibodies in wild-type mice did not lead to fluorescence within the brain. Overall, these findings (and the other data presented in the paper) indicate that leakage of the BBB in the P301L model coupled with neuronal uptake of the antibodies may explain the positive effects of the immunotherapy.

Several studies have shown neuronal uptake of antibodies, and a few receptors that can bind immunoglobulins have been identified on neurons. It can be postulated that as a consequence of P301L tau-mediated neurodegeneration, the endosomal-lysosomal system is activated, which may facilitate uptake of antibodies into endosomes. Aggregated tau should be in the lysosomes and once those fuse with the endosomes, antibody binding to tau should facilitate tau degradation.

It is interesting to note that in our hands, normal neurons do not appear to take up appreciable amounts of antibodies, as we have not observed uptake/binding of anti-tau antibodies in neuroblastoma cells and primary cultures that do not have tau pathology. This observation suggests that side effects of this type of therapy are less likely, as normal neurons are not targeted.

I should also mention, as referenced in the article, that while these studies were underway or being reviewed, reports by Masliah et al. (1) and Tampellini et al. (2) further support our findings and interpretations.

References:

1. Masliah,E., Rockenstein,E., Adame,A., Alford,M., Crews,L., Hashimoto,M., Seubert,P., Lee,M., Goldstein,J., Chilcote,T., Games,D., and Schenk,D., Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease, Neuron, 46 (2005) 857-868. Abstract

2. Tampellini,D., Magrane,J., Takahashi,R.H., Li,F., Lin,M.T., Almeida,C.G., and Gouras,G.K., Internalized antibodies to the A beta domain of APP reduce neuronal Abeta and protect against synaptic alterations, J. Biol. Chem., 282 (2007) 18895-18906. Abstract

View all comments by Einar Sigurdsson

A very provocative paper. It will be interesting to see if this approach can delay the pathological progression and memory loss in an inducible mouse model of tauopathy (rTg4510) without the severe motor dysfunction that is known to develop in the JNPL3 mouse strain.

View all comments by Leonard Petrucelli