Tau Vaccine Detangles Mouse Brain
Vaccination is not just for amyloid anymore, according to new work out this week from Einar Sigurdsson and colleagues at the New York University School of Medicine in New York. In the August 22 Journal of Neuroscience, the researchers report that immunizing mice with a phospho-tau peptide results in a specific antibody response, less brain tau pathology, and better performance on motor tasks. Tau tangles are companion lesions to the amyloid plaques of Alzheimer disease, and by themselves cause frontotemporal dementias. The results, which were presented in preliminary form last year in Madrid (see ARF meeting story), indicate that immunotherapy may be a viable option for clearing tau deposits in these diseases, even though the deposits occur inside cells.
In the work, first author Ayodeji Asuni immunized homozygous P301L mutant tau-expressing mice, a strain that has a rapid and massive buildup of hyperphosphorylated, aggregated tau reminiscent of frontotemporal dementia in humans. Vaccination with a phospho-tau peptide led to the production of antibodies that recognized the immunogen, and pathological tau on brain sections. Immunizing young animals starting at 2 months of age led to reductions in tau histopathology at 5 or 8 months, in some brain regions by as much as 96 percent. The greatest reduction was seen in tau aggregates recognized by the MC1 antibody, an earlier stage of tau pathology compared to the paired helical filaments picked up by the PHF1 antibody, which were also reduced but not as dramatically.
The clearance of tau was associated with behavioral improvements in the mice, who normally lose motor skills as tau accumulates. At 5 months of age, the immunized mice displayed better balance on a rotating rod and an elevated beam. The effects diminished with time: by 8 months of age, the immunized animals still performed better than controls, but their abilities had decreased compared to 5 months. Because of their profound motor deficits, extensive cognitive testing is difficult in these mice, and other models will be needed to assess the effect of tau removal on learning and memory.
How might vaccination clear tau from neurons? The researchers showed that the antibodies generated in immunized animals are capable of entering the brain, possibly because tauopathy compromises the blood-brain barrier. Once there, antibodies can be taken up by cells by one of several endocytic pathways, and the investigators show co-localization of antibodies with pathological tau deposits. In the cells, Sigurdsson speculates, the antibodies serve to promote disassembly and degradation of tau assemblies. “In my opinion, the antibodies are more likely to clear smaller assemblies of tau aggregates than tangles," he told ARF. However, a separate, detailed study on tau forms present in brains of treated mice will be required to establish just which forms are targeted by immunotherapy. Nonetheless, tau makes the second case of successful immunization against intracellular neuronal proteins, the first being vaccination against α-synuclein, a cause of Parkinson disease (see ARF related news story).
The P301L homozygous animals used for the studies have an aggressive tau pathology, where tangles show up by 5 months and the animals are nearly completely paralyzed by 12 months. That the vaccine is effective at slowing disease progression leads Sigurdsson to speculate that it may work even better in animals with a slower, more AD-like accumulation of tau. In such models, immunization may have a better chance to clear small tau aggregates prophylactically, he suggests. The researchers plan to follow up their results by testing multiple immunogens and other models of tauopathy, such as the human tau mice where pathology develops more slowly (Andorfer et al., 2003). Also in the works are studies in AD mouse models that have both amyloid and tau pathology. Ultimately, Sigurdsson says, he wants to test combined immunization for amyloid and tau, lobbing a double whammy against the lesions that appear to act together to cause the symptoms of AD.—Pat McCaffrey
- Madrid: BACE News Roundup, Part 2
- Clearing Aggregates—Macrophages Fall Short for Aβ, but Vaccine Mops Up α-synuclein
- Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem. 2003 Aug;86(3):582-90. PubMed.
- Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci. 2007 Aug 22;27(34):9115-29. PubMed.
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University of Pennsylvania
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
New York University School of Medicine
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.
Masliah E, Rockenstein E, Adame A, Alford M, Crews L, Hashimoto M, Seubert P, Lee M, Goldstein J, Chilcote T, Games D, Schenk D. Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron. 2005 Jun 16;46(6):857-68. PubMed.
Tampellini D, Magrané J, Takahashi RH, Li F, Lin MT, Almeida CG, Gouras GK. Internalized antibodies to the Abeta domain of APP reduce neuronal Abeta and protect against synaptic alterations. J Biol Chem. 2007 Jun 29;282(26):18895-906. PubMed.View all comments by Einar Sigurdsson
Mayo Clinic College of Medicine
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
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