Immunotherapy Targeting Pathological Tau Protein in Alzheimer's Disease and Related Tauopathies

Abstract

Immunotherapies that target the amyloid-β (Aβ) 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 Aβ 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, Aβ 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 tanglerelated 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.

P1‐355: Mechanistic studies of antibody mediated clearance of tau aggregates using an ex vivo brain slice model

“…Moreover, using immuno electron microscopy techniques, Meeker et al (1987) showed that antibodies could be detected within lysosomes. Thus, we propose that the antibody-mediated removal of tau aggregates is facilitated by clearance through the endosomal-lysosomal pathway (Sigurdsson, 2008(Sigurdsson, , 2009.…”

Opportunities for Conformation-Selective Antibodies in Amyloid-Related Diseases

“…It binds to tubulin and acts as a stabilising agent during polymerisation into microtubules in neurones. However, as a result of post-translational modifications, including hyperphosphorylation, glycosylation, ubiquitination, glycation, polyamination, nitrosylation, and truncation, the tau protein can undergo a transformation from an unfolded into a higher order structure prone to aggregation and subsequent fibrilisation [70][71][72][73]. Normal tau contains 2-3 mol phosphate/mol of the protein [70].…”

“…Thus design of antibodies targeting specific motifs associated with the toxic species is paramount in order to avoid disastrous consequences, such as destabilization of the microtubes and subsequent interference with axonal transport and cytoskeletal integrity [27][28][71][72][73]. One of the approaches is to design an antibody to target the phosphorylation sites that are characteristic for toxic species.…”

“…In contrast, phosphorylation at ser202 and thr205 has been related to late phospho-tau changes. An alternative is to target conformations that are only associated with the aggregated forms of tau [71][72][73]. Additionally, as tau aggregates are formed, antibodies can take an advantage from the avidity effect and increase the apparent selectivity for toxic species over tau monomer.…”

Chemical and Physical Approaches for the Treatment of Alzheimer's Disease

“…Sigurdsson and his colleagues suggested that anti-phospho tau antibodies could inhibit brain aggregated tau and suppress progression of tangle-related behavioural phenotype in mouse models [96].…”