Alzheimer's disease is one of several neurodegenerative diseases known as tauopathies because they involve the formation of intracellular aggregates of tau, a microtubulus binding protein. Unfortunately, however, despite promising results in preclinical studies, tau immunotherapies have failed to improve patients' cognitive abilities.
We may not yet understand which tau antibodies can truly remove pathogenic tau from the brain. In a recent paper published in Science, Aamir Mukadam and colleagues demonstrated that the cytoplasmic antibody receptor TRIM21 (tripartite motif-containing 21), which simultaneously has E3 ubiquitin ligase activity, is necessary for effective tau immunotherapy. The tau antibodies used in this work bind with pathogenic tau aggregates in the extracellular environment of neurons and lead to their degradation in the neurons themselves.
Cellular uptake of the antibodies occurs after interaction with superficial heparan sulfate proteoglycans and low-density lipoprotein receptor-related protein 1 (LRP1). Cytoplasmic TRIM21 receptor then stimulates degradation of the tau-antibody complex involving the proteasome, the cellular 'garbage can'. This prevents pathological tau accumulation in neurons.
Fig. Tau antibodies can recognize pathogenic tau fibrils (seeds) in the extracellular environment. After binding, the antibody complex is internalized not only by microglial cells via Fc receptors, but also via LDL and heparan sulfate receptors on neurons. In these, pathological tau is ubiquitinated in the cytoplasm via tripartite motif 21 (TRIM21) and degraded in the proteasome.
Previously, it was assumed that the internalization of anti-tau by microglia occurs with the help of binding sites on the cell surface, the Fc-γ receptors (FcγRs). Unexpectedly, however, immunotherapeutic treatment with modified tau antibodies, which have only reduced binding to microglial antibody receptors, now showed a reduction in tau deposition in particular.
Mukadam et al. used a transgenic mouse model expressing human mutant tau for their experiments. Treatment of organotypic slice cultures of the hippocampus with the monoclonal tau antibody BR134 resulted in a marked reduction in extracellular tau aggregates. However, when TRIM21 was removed or the proteasome was blocked, treatment with BR134 failed to reduce aggregates. Furthermore, treatment with the tau-specific monoclonal antibody AP422 resulted in reduced tau pathology in animals with mutant tau but not in TRIM21-deficient tau transgenic mice.
Because the behavior of the animals was not examined in the publication, it is not yet clear whether TRIM21-mediated removal of the tau-antibody complex can actually improve the cognition of the mice. In addition, we do not yet understand the exact mechanism of antibody-tau complex internalization into neurons. It would also need to be tested whether free antibodies can be taken up to bind intraneuronal tau. Overall, however, the present results refute the previous assumption that activation of microglia is required for the efficacy of tau immunotherapy.
References:
Mukadam AS, Miller LVC, Smith AE, ... , James LC, McEwan WA (2023) Cytosolic antibody receptor TRIM21 is required for effective tau immunotherapy in mouse models. Science 379:1336
Nisbet RM (2023) Effective immunotherapy occurs in neurons. Science 379:1300
Image credit: iStock/peterschreiber.media
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