Tau-based treatment strategies in neurodegenerative diseases.
Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.
Schneider
Anja
A
Department of Psychiatry and Psychotherapy, Von-Siebold-Strasse 5, University of Goettingen, Goettingen, Germany.
Mandelkow
Eckhard
E
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007167:Immunotherapy; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000276:immunology* / Q000378:metabolism*
D000906:Antibodies; D016875:tau Proteins