From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy

• Published in: Acta neuropathologica Vol. 139; no. 1; pp. 3 - 25
• Main Authors: Colin, Morvane, Dujardin, Simon, Schraen-Maschke, Susanna, Meno-Tetang, Guy, Duyckaerts, Charles, Courade, Jean-Philippe, Buée, Luc
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2020; Springer; Springer Nature B.V; Springer Verlag
• Subjects: Alzheimer's disease; Animal models; Animals; Cell culture; Clinical trials; Development and progression; Geriatry and gerontology; Health aspects; Human health and pathology; Humans; Hypotheses; Immunotherapy; Immunotherapy - methods; Life Sciences; Medicine; Medicine & Public Health; Neurodegenerative diseases; Neuroimaging; Neurons and Cognition; Neurosciences; Paralysis; Pathology; Prions; Progressive supranuclear palsy; Propagation; Proteostasis Deficiencies - pathology; Proteostasis Deficiencies - therapy; Review; Tau protein; Tauopathies - pathology; Tauopathies - therapy; Tissues and Organs; Plasma; Alzheimer’s disease; Progressive supranuclear palsy; Secretion; Immunotherapy; CSF; Tau; Seeding
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-019-02087-9

The term “propagon” is used to define proteins that may transmit misfolding in vitro, in tissues or in organisms. Among propagons, misfolded tau is thought to be involved in the pathogenic mechanisms of various “tauopathies” that include Alzheimer's disease, progressive supranuclear palsy, and argyrophilic grain disease. Here, we review the available data in the literature and point out how the prion-like tau propagation has been extended from Alzheimer's disease to tauopathies. First, in Alzheimer’s disease, the progression of tau aggregation follows stereotypical anatomical stages which may be considered as spreading. The mechanisms of the propagation are now subject to intensive and controversial research. It has been shown that tau may be secreted in the interstitial fluid in an active manner as reflected by high and constant concentration of extracellular tau during Alzheimer’s pathology. Animal and cell models have been devised to mimic tau seeding and propagation, and despite their limitations, they have further supported to the prion-like propagation hypothesis. Finally, such new ways of thinking have led to different therapeutic strategies in anti-tau immunotherapy among tauopathies and have stimulated new clinical trials. However, it appears that the prion-like propagation hypothesis mainly relies on data obtained in Alzheimer’s disease. From this review, it appears that further studies are needed (1) to characterize extracellular tau species, (2) to find the right pathological tau species to target, (3) to follow in vivo tau pathology by brain imaging and biomarkers and (4) to interpret current clinical trial results aimed at reducing the progression of these pathologies. Such inputs will be essential to have a comprehensive view of these promising therapeutic strategies in tauopathies.