Immunotherapy targeting pathological tau protein in Alzheimer's disease and related tauopathies

Abstract

Immunotherapies that target the amyloid-beta (Abeta) peptide in Alzheimer's disease (AD) have shown promise in animal and human studies. Although the first clinical trial was halted because of adverse reactions, this approach has been refined and additional trials are underway. Another important target in AD is the neurofibrillary tangles, composed primarily of hyperphosphorylated tau proteins, which correlate well with the degree of dementia. As Abeta and tau pathologies are likely synergistic, targeting both should be more effective and may be essential as early diagnosis prior to cognitive decline is currently not available. Also, Abeta immunotherapy only results in a very limited indirect clearance of tau aggregates in dystrophic neurites, showing the importance of developing a separate therapy that directly targets pathological tau. Our findings in two tangle mouse models indicate that immunization with a phospho-tau derivative reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. These antibodies enter the brain and bind to pathological tau within neurons. We are currently clarifying further the mechanism of action of this promising therapeutic approach and determining its epitope specificity.

Figure 1. Potential mechanisms for clearance of pathological tau within neurons

A: 1) Aggregated tau within neurons activates protein quality control mechanisms within neurons which results in the generation of phagosomes that encapsulate the aggregates. 2) Anti-tau antibodies are transported into the cell via receptor-mediated endocytosis through the Thy 1.1 receptor, the lipoprotein receptor-related protein (LRP) and/or the Fc receptor (FcR). 3) The antibody-endosomes fuse with the tau-phagosomes and, 4) subsequently fuse with lysosomes in which 5) the antibodies and the tau aggregates are degraded. B: Anti-tau antibodies may enter the neuron through passive diffusion that may be more prominent in damaged neurons. 1) Tau aggregates are often found near the inner lumen of the neuronal plasma membrane by which they could bind to the antibodies. 1) The complex would then be engulfed by endosomes/phagosomes, 2) fuse with lysosomes and, 3) be degraded as in A.