Tau-Based Treatment Strategies in Neurodegenerative Diseases

Abstract

Summary: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.

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…Regarding therapy, the Tau-based research has led to several approaches (reviewed by Schneider and Mandelkow 2008;. They are directed against hyperphosphorylation (e.g., the search for kinase inhibitors or phosphatase enhancers), aggregation (e.g., aggregation inhibitors), compounds promoting microtubule stability (to compensate for Tau dysfunction), and Tau-based immunotherapy.…”

“…A number of excellent reviews on the biology and pathology of Tau have appeared over the past few years (Cassimeris and Spittle 2001;Garcia and Cleveland 2001;Terwel et al 2002;Dehmelt and Halpain 2005;Andreadis 2006;Ballatore et al 2007;Gotz et al 2007Gotz et al , 2010Schneider and Mandelkow 2008;Sergeant et al 2008;Aguzzi and Rajendran 2009;Spires-Jones et al 2009;Iqbal et al 2009;Wolfe 2009;Goedert et al 2010;Morris et al 2011;Salminen et al 2011). This brief review will cover a few salient aspects, with an emphasis on Tau structure and interactions.…”

Prostate-derived Sterile 20-like Kinases (PSKs/TAOKs) Phosphorylate Tau Protein and Are Activated in Tangle-bearing Neurons in Alzheimer Disease

“…In previous studies, phosphorylated tau residues have been divided into two types according to their location (37). The first type includes residues located in the tau microtubule-binding domain (amino acids 244 -368) and are involved in regulating tau-microtubule interactions, and the second type includes residues located in the regions flanking this domain that are also abnormally phosphorylated in AD (37).…”

“…The first type includes residues located in the tau microtubule-binding domain (amino acids 244 -368) and are involved in regulating tau-microtubule interactions, and the second type includes residues located in the regions flanking this domain that are also abnormally phosphorylated in AD (37). The phosphorylation and detachment of tau from microtubules are likely to contribute to the aggregation of insoluble tau into PHFs, and we have shown here that PSK1-␣/␤ and PSK2 can phosphorylate nine and 12 sites, respectively, within the tau microtubule-binding domain.…”

“…To date, the main candidate kinase for the phosphorylation of tau on Ser-262/Ser-356 is MARK, but the ability of PSKs to target these KXGS motifs either directly and/or indirectly via the stimulation of MARK suggests a potential role for PSKs in the phosphorylation of tau on these sites (14,41). Either way, although the phosphorylation of KXGS motifs and the dissociation of tau from microtubules appear to be important in AD pathogenesis, they are not sufficient by themselves to generate PHF-tau in vitro (37). It has been suggested that cytosolic tau may be more accessible than microtubule-bound tau to phosphorylation on additional sites and that the hyperphosphorylation of tau may be required to form PHFs (37).…”