Trends in Cell Biology
ReviewConnecting the dots between tau dysfunction and neurodegeneration
Section snippets
Involvement of tau in neurodegenerative diseases
In 1907, Alois Alzheimer first described neurofibrillary tangles [1], which are now known to be a key pathological feature of a number of neurodegenerative diseases. Eight decades later the major component of neurofibrillary tangles was identified, a hyperphosphorylated, filamentous form of the tau protein [2]. The subsequent discovery of a group of inherited tauopathies, termed frontotemporal dementia with parkinsnism associated with chromosome 17 (FTDP-17), that are caused by dominant
Mechanisms of tau neurotoxicity
The aggregation of misfolded tau protein, the autosomal dominant inheritance pattern in familial tauopathies 3, 4, 5, and the lack of an obvious neurodegenerative phenotype in tau knockout animal models [10], suggests a dominant gain of function pathogenic mechanism. Accordingly, transgenic expression of human wild type or mutant tau causes progressive neuronal death in various animal models of tauopathy 11, 12. These models have enabled identification and characterization of key cellular
Concluding remarks and future directions
There is a significant unmet need for therapies that slow or prevent the progression of tauopathies. As the most common tauopathy, AD has been the focus of multiple past and recent clinical trials, with disappointing results (Table 1). Current treatments for AD (cholinesterase inhibitors and NMDA receptor antagonists) modestly and temporarily reduce symptoms associated with the disease but do not stop disease progression [85]. Table 1 summarizes human clinical trials, drugs that have been
Acknowledgments
B.F. is supported by the US National Institute of Neurological Disorders and Stroke (NINDS; K99NS088429). J.G. is supported by the Australian Research Council (DP13300101932) and the National Health and Medical Research Council of Australia (APP1037746, APP1003150). M.B.F. is supported by the US National Institute on Aging (NIA; R21AG040796 and R01AG044113) and NINDS (R01NS083391 and R01NS083391).
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2020, Neurobiology of AgingCitation Excerpt :Recent studies suggest that hyperphosphorylated tau may mediate early synaptic deficits before the manifestation of neurodegeneration or deposition of NFTs (Chong et al., 2011; Hoover et al., 2010; Liao et al., 2014). Zempel and Mandelkow (2014) showed that tau sorting mechanisms fail and tau becomes missorted into the somatodendritic compartment (Kobayashi et al., 2017), whereas in healthy neurons, the highest concentration of tau is present in the axonal compartment, where it stabilizes microtubules and mediates microtubule-related processes, for example, transport of proteins, organelles, vesicles (Jaworski et al., 2011), and maintenance of the cytoskeleton (Elie et al., 2015; Frost et al., 2015). Moreover, recent studies show that tau interacts with the actin cytoskeleton (Elie et al., 2015) and that actin dynamics are significantly distorted by tauopathies because of the promotion of actin bundling (Frost et al., 2015).