. Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. Sci Rep. 2015 Jun 9;5:11161. PubMed.


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  1. In this Scientific Reports publication, Steve Paul and colleagues demonstrate microglial degradation of pathological tau in a number of in vitro and ex vivo paradigms, including incubation of human brain sections with primary mouse microglia. They also show enhancement of this degradation by MC1, an antibody binding to pathological tau, and suggest that this effect is Fc-mediated, because the MC1 Fab fragment is not active in the assay. The paper does not address whether the Fab fragment is less active due to loss of effector function or loss of the avidity benefit of an antibody.

    Overall, these are exciting new data reminiscent of and in line with work on microglial-mediated Aβ plaque clearance from 2000 on from, e.g., Bard et al. (Bard et al., 2000), Steve’s group, and others.

    It now remains to be shown whether this mechanism plays out for tau in vivo. This is not straightforward: Passive immunization data presented by the Genentech/AC Immune team at the last ADPD meeting showed equal efficacy of full effector or effectorless antibodies in a P301L transgenic model (Ayalon et al., abstract 1499), suggesting that, at least for their antibody, induction of microglial clearance is not a critical contributor to efficacy.

    Clearly, more work is needed to fully understand the mechanisms of tau clearance and tau immunotherapy in cell systems and in vivo.


    . Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. 2000 Aug;6(8):916-9. PubMed.

    View all comments by Martin Citron
  2. While many studies have shown that active and passive tau immunization successfully attenuate tau pathology in tauopathy model mice, the underlying mechanism is poorly understood. Recent evidence suggests that pathological tau species secreted from affected neurons are taken up by the connecting neurons in which internalized tau aggregates promote de novo aggregation by endogenous soluble tau, which explains how tau pathology spreads in the brain. This hypothesis implies that anti-tau antibodies attenuate tau pathology by sequestering extracellular tau and thereby preventing tau pathology propagation. In the present study, Luo et al. clearly demonstrate that brain microglia also participate in the clearance of extracellular tau. Mouse primary microglia were shown to rapidly internalize and degrade tau aggregates derived from AD brain. Furthermore, an anti-tau monoclonal antibody, but not its Fab fragment, facilitated this degradation, suggesting that microglia internalize extracellular tau not only by phagocytosis but also by Fc receptor-mediated endocytosis of immune complexes. A similar phenomenon was previously observed with Aβ.

    Thus, the present study gives the opportunity to investigate the clearance mechanism for extracellular tau in comparison with that for Aβ. Four possible mechanisms have been proposed for Aβ clearance: 1) degradation by membrane-bound or extracellular enzymes such as neprilysin and insulin-degrading enzyme, 2) internalization into neuronal/glial cells and degradation in the lysosomes, 3) receptor-mediated transcytosis at the blood-brain barrier and efflux into the blood, and 4) efflux into the CSF or lymph nodes through the perivascular lymphatic drainage. The present study indicates that the first mechanism is unlikely for tau, since conditioned media of microglia contained little tau-degrading activity. The second mechanism is the most plausible in tau clearance. Microglia were shown to internalize and degrade extracellular tau, and antibodies enhanced this process. The latter finding cautions that Fc-truncated versions of IgG such as single-chain Fv might have lower clearance activity against extracellular tau despite their higher efficacy to enter the brain. Moreover, this notion would prompt us to select antibodies with a higher binding affinity to Fc receptors during the development of therapeutic antibodies. Notably, when microglial cells were cultured for 24 hours on unfixed frozen brain sections prepared from tauopathy mice, AT8-positive intracellular tau aggregates (the authors assumed these aggregates were NFTs, but strictly speaking, NFTs should be identified by silver staining) in the sections were significantly reduced. It is surprising that such a rapid elimination (within 24 hours) of intracellular tau aggregates could be achieved only by removing extracellular tau. This finding suggests that intracellular tau is in dynamic equilibrium with extracellular tau. As for the third and fourth mechanisms, their involvement in tau clearance is unclear.

    Several studies have shown that antibodies injected into model mice can eliminate pre-existing intracellular tau aggregates, including NFTs. This mechanism is largely unknown. Antibodies may penetrate into cells passing through the plasma membrane and clear tau aggregates in the cytoplasm. Alternatively, there may be a dynamic equilibrium between intracellular and extracellular tau, as mentioned above. Antibodies may shift this equilibrium to induce tau efflux from cells by removing extracellular tau, leading to the eventual elimination of intracellular NFTs. It has been proposed that some misfolded protein pathology spreads in the brain via exosome release from affected cells or tunneling nanotube formation between cells. Whether these mechanisms also contribute to tau pathology propagation, and whether antibodies have any function against them, might be an issue in tau immunotherapy research.

    View all comments by Takami Tomiyama
  3. Recently, immunotherapy has emerged as a promising approach to target tau, but many mechanistic questions remain regarding how such immunotherapy works. Some of these questions pertaining to mechanism of action of immunotherapy are tightly linked to the potential relative contribution of mechanisms that underlie induction and spread of tau pathology. “Spread” of tau inclusion pathology may result from a combination of mechanisms that includes cell autonomous intrinsic disruption of proteostasis and non-cell autonomous mechanisms — seeding from extracellular tau and induction of a toxic environment induced either by extracellular tau acting as an inflammogen, or by induction of a generalized toxic environment that disrupts proteostasis. Strong data have emerged that antibodies may reduce tau pathology by targeting extracellular tau seeds or by binding, and directly target intracellular tau. It is unclear whether effector function is beneficial for antibodies’ efficacy in vivo. Given these data and the uncertainties regarding the mechanisms of induction and spread of tau pathology in human brain and mouse models of human tauopathies, it is challenging to definitively determine antibody mechanism of action in the disease modification.

    The findings in this new paper by Luo et al. are very intriguing, clearly pointing to the fact that antibody presence facilitates microglia-mediated reduction in the levels of pathological tau. It is possible that one of the mechanisms by which passive and active immunization works involves stimulating tau phagocytosis by microglia. However, one has to be cautious in speculating that full antibody presence is essential for potential therapeutic approach in vivo, given the recent findings that Fab fragments (Genentech) as well as scFvs (Levites) are efficient in reducing tau pathology, at least in transgenic mouse models.

    In conclusion, more studies have to be done looking at various phospho-tau and conformation-specific tau binding in order to rule out the main mechanism by which tau immunotherapy works.

    View all comments by Yona Levites
  4. This manuscript provides support for the classical concept that microglia cells perform an important homoeostatic activity in CNS. In the context of anti-tau immunotherapy, the findings strengthen the hypothesis that certain antibodies may reduce intracellular tau pathology by acting extracellularly, through neutralization and opsonization of toxic misfolded/aggregated tau species, which may then be cleared by phagocytosis. Therefore, it is conceivable that antibody candidates in development might benefit from retaining their effector function.

    The concept that "epitope matters” most likely applies to tau immunotherapy, as it does for other misfolded protein targets in CNS.

    View all comments by Wagner Zago
  5. Thanks to Jessica Shugart for writing a nice summary of our paper and for Martin Citron's thoughtful comments. I'd like to underscore that we are not stating that anti-tau monoclonal antibodies work to reduce tau pathology by an effector-mediated microglial clearance mechanism. What we observed is that for this specific antibody (MC1), using in vitro/ex vivo brain section assays, we saw a stimulation of tau uptake/degradation by the antibody that we did not observe for the Fab. It will take considerably more work to know whether effector function plays any role, good or bad, in the now widely reproduced in vivo effects of anti-tau monoclonal antibodies, i.e., in reducing tau pathology in mouse tauopathy models.

    To this day, there are similar debates, and even contradictory data, about anti-Aβ/amyloid monoclonal antibodies. Do they require effector function or not ? My guess is that it is clearly a function to be enhanced, reduced, or potentially eliminated for optimizing tau monoclonal antibodies for therapeutic purposes, but exactly what to do (i.e., what is the optimal antibody?) will require much more work and may not be completey clear until we generate some clinical data in AD/FTD patients.

    Our work does highlight a potential role for microglia in clearing extracellular tau species and adds to a growing body of literature suggesting a critical role for microglia in AD pathogenesis. We would caution again, however, that we will need in vivo data to substantiate the hypothesis that microglia function normally to reduce the spread or pathogenicity of tau (several experiments are underway). We are using these assays to also screen for compounds that might enhance microglial-mediated degradation of tau and other pathological/misfolded proteins that clearly play a role in neurodegenerative disorders.

    View all comments by Steven Paul

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  1. Antibodies Boost Microglial Appetite for Tau