Trends in Cell Biology
Volume 25, Issue 1, January 2015, Pages 46-53
Journal home page for Trends in Cell Biology

Review
Connecting the dots between tau dysfunction and neurodegeneration

https://doi.org/10.1016/j.tcb.2014.07.005Get rights and content

Highlights

  • Downstream mechanisms of tau neurotoxicity are discussed.

  • Tau drives cytoskeletal, mitochondrial, chromatin, and cell cycle dysfunction.

  • Processes connecting tau dysfunction to apoptosis are potential therapeutic targets.

Tauopathies are devastating and ultimately fatal neurodegenerative diseases, which are histopathologically defined by insoluble filamentous deposits of abnormally phosphorylated tau protein within neurons and glia. Identifying the causes of abnormal tau phosphorylation and subsequent aggregation has been the focus of much research, and is currently a major target for the development of therapeutic interventions for tauopathies, including Alzheimer's disease (AD). Much has recently been learned about the sequence of events that lead from tau dysfunction to neuronal death. This review focuses on the cascade of events that are catalyzed by pathological tau, and highlights current and potential therapeutic strategies to target this pathway.

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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      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).

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