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Tauopathies are neurodegenerative brain diseases that are characterized by the formation of intraneuronal inclusions containing the microtubule-associated protein tau. This major hallmark defines tau pathology which is predominant in primary tauopathies, while in secondary forms additional driving forces are involved. In the course of the disease, different brain areas degenerate and lead to severe defects of language, behavior and movement. Although neuropathologically heterogeneous, primary tauopathies share a common feature, which is the generation of abnormal tau species that aggregate and progress into filamentous deposits in neurons. Mechanisms that are involved in this disease-related process offer a broad range of targets for disease-modifying therapeutics. The present review provides an up-to-date overview of currently known targets in primary tauopathies and their possible therapeutic modulation. It is structured into four major targets, the post-translational modifications of tau and tau aggregation, protein homeostasis, disease propagation, and tau genetics. Chances, as well as obstacles in the development of effective therapies are highlighted. Some therapeutic strategies, e.g., passive or active immunization, have already reached clinical development, raising hopes for affected patients. Other concepts, e.g., distinct modulators of proteostasis, are at the ready to be developed into promising future therapies. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.

International audience; Both genetic and environmental factors likely contribute to the neuropathology of tauopathies, but it remains unclear how specific genetic backgrounds affect the susceptibility towards environmental toxins. Mutations in the tau gene have been associated with familial tauopathies, while annonacin, a plant-derived mitochondrial inhibitor, has been implicated in an environmental form of tauopathy. We therefore determined whether there was a pathogenic synergy between annonacin exposure and the expression of the R406W-tau mutation in transgenic mice. We found that annonacin exposure caused an increase in the number of neurons with phosphorylated tau in the somatodendritic compartment in several brain areas in R406W(+/+) mice as opposed to mice that had only the endogenous mouse tau (R406W(-/-)). Western blot analysis demonstrated a concomitant increase in total tau protein without increase in tau mRNA, but reduced proteasomal proteolytic activity in R406W(+/+), but not R406W(-/-) mice, upon annonacin-treatment. Phosphorylated tau levels exceeded the increase in total tau protein, along with increased levels of different tau kinases, foremost a striking increase in the p25/p35 ratio, known to activate the tau kinase Cdk5. In summary, we observed a synergistic interaction between annonacin exposure and the presence of the R406W-tau mutation, which resulted in reduced degradation, increased phosphorylation and redistribution of neuronal tau.

Neuregulin-1 (NRG1) belongs to a large family of growth and differentiation factors with a key role in the development and maintenance of the brain. Genetic association of NRG1 within brain disorders such as Alzheimer's disease, schizophrenia and neuroprotective properties of certain NRG1 isoforms have led to a variety of studies in corresponding disease models. In the present work, we investigated NRG1 with regard to its peripheral and central biodistribution after systemic application. We first-time radiolabeled the entire biologically active extracellular domain of NRG1 isotype-β1 (NRG1-β1 ECD; aa 2-246) with iodine-125 and administered it peripherally to healthy adult C57Bl6 mice. Blood kinetics and relative organ distribution of (125)I-labeled NRG1-β1 ECD were determined. The blood level of NRG1-β1 ECD peaked within the first hour after intraperitoneal (i.p.) application. The brain-blood ratios of (125)I-labeled NRG1-β1 ECD were time-dependently 150-370% higher compared to the brain impermeable control, (131)I-labeled bovine serum albumin. Autoradiographs of brain slices demonstrated that (125)I-labeled NRG1-β1 ECD accumulated in several regions of the brain e.g. frontal cortex, striatum and ventral midbrain containing the substantia nigra. In addition we found histochemical and biochemical evidence that phosphorylation of the NRG1 prototype receptor ErbB4 was increased in these regions after systemic application of NRG1-β1 ECD. Our data suggest that NRG1-β1 ECD passes the blood-brain barrier and activates cerebral ErbB4 receptors.