Tau neurotoxicity and rescue in animal models of human Tauopathies
Introduction
Tau, a microtubule-associated protein discovered in Marc Kirschner's lab [1], is located mainly in neurons. It is ubiquitously distributed in immature neurons but becomes axonal during maturation [2, 3]. Major interaction partners of Tau are microtubules, but a number of other interaction partners have emerged including actin filaments, neurofilaments, protein kinases, motor proteins and others (see also [4]). Thus Tau is much more versatile than originally anticipated. It can be found inside or outside of neurons, or located in axons or dendrites while interacting with different targets. Abnormal changes in Tau are hallmarks of pathological conditions in neurons, and Tau may mediate pathological reaction cascades. This holds for ‘classical Tauopathies’ including Alzheimer disease (AD), frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Knocking out Tau in models of AD [5], epilepsy [6, 7•] or traumatic brain injury (TBI) [8] can suppress pathology. Tau can become harmful to synapses, leading to cognitive impairment and neuronal death [9, 10]. In search for the toxic species of Tau, current evidence points to soluble (probably oligomeric) forms rather than neurofibrillary tangles (NFTs) (for review see [11•]). The stereotypic progression of Tau pathology between connected brain regions has been observed long ago [12, 13] but the underlying mechanism of transmission is still a mystery. We discuss evidence that suggests that excitotoxicity, oxidative stress or inflammation can promote protein misfolding of Tau, but also describe the hypothesis that Tau pathology might spread through a prion-like mechanism of templated propagation of a misfolded conformation. The extracellular and transsynaptic spreading of toxic species of Tau dominates current discussions [14•]. Hence, Tau-directed immunotherapy has experienced a boom in recent years. In this review we focus on the cellular functions and pathological mechanisms of Tau in preclinical studies, but not on clinical aspects. Therefore we do not cover the use of Tau in the cerebrospinal fluid (CSF) as an early biomarker for AD and other Tauopathies, or the recent revolution in the development of PET ligands for imaging Tauopathy in the brains of patients. Excellent reviews of these areas can be found elsewhere [15, 16].
Section snippets
Soluble oligomeric forms of Tau can be toxic
A strong indication that soluble forms of Tau are responsible for toxicity comes from switch-off experiments in transgenic Tau mice. Memory deficits were reversible when Tau transgene expression was suppressed, even in the continued presence of NFTs [17, 18]. Likewise, in rTg4510 mice (expressing P301L Tau) structural and electrophysiological impairment of neurons did not depend on the presence of NFTs [19]. Invariably these mice showed abnormalities in synaptic function prior the appearance of
Tau oligomers impair cognition in humans
Further proof is provided by human studies, which showed that a substantial proportion of the elderly population develops NFTs and Aß plaques without experiencing dementia [20, 21]. These studies revealed (consistent with results from transgenic mice) that hyperphosphorylated soluble Tau species (localized in synapses) are probably mediators of neurotoxicity and altered cognition. The accumulation of prefibrillar Tau oligomers correlates with cognitive decline in people suffering from mild
Transmission of Tauopathy
Tau pathology spreads in the brain of AD patients in a well-defined manner, so that its distribution can be correlated with the clinical stages of the disease [12]. Several hypotheses have been proposed to explain the stereotypical propagation. They include lack of growth factors, inflammation, oxidative stress, excitotoxicity or prion-like mechanisms [23, 24, 25•, 26]. The direct protein transfer is supported by recent data from transgenic mice. The design of animals with a restricted
Tau is released from living cells
Tau is physiologically released from presynaptic terminals in vitro and in vivo in an activity-dependent manner [32•, 33•]. Wild-type human Tau spreads more efficiently than mutant Tau after lentiviral transfection in rats [34]. This leads to the question whether extracellular Tau meets a physiological function (e.g. in neuronal signaling, see Figure 1), and whether pathological Tau uses the same or a different pathway. In the murine ISF, Tau is found as a naked protein [30], whereas in a cell
Prion-like mechanism of spreading
One hypothesis is that affected neurons release Tau in a pathological conformation, which is taken up by another cell and thus ‘seeds’ the conversion to pathological aggregation-prone protein, reminiscent of what has been proposed for the spreading of prion protein [36, 37, 75]. One example of transfer is that extracellular Tau binds to heparan sulfate proteoglycans (HSPGs) on the surface of receiving cells where they mediate the import from outside. Once it has entered the cell, pathological
Pathological Tau reduces network activity
In vivo recordings in mice expressing mutant Tau (rTg4510, mutation P301L) displayed a disrupted spontaneous activity and reduced firing rates of neocortical neurons [40]. Another line expressing aggregation-prone Tau (mutation ΔK280) alters presynaptic morphology (e.g. depletion of synaptic vesicle pool) and function of the mossy fibers, which also affected postsynaptic neurons [41]. Mice expressing the V337M mutant of Tau showed an NMDA receptor hypofunction, and pathology could be prevented
Endogenous Tau regulates hyperexcitability
Evidence from Tau knockout (TKO) mice suggests that (endogenous) Tau plays a key role in neuronal hyperexcitability [6, 7•, 44, 45]. For example, knocking out Tau in adult mice protects them against epileptiform activity [7•]. The strength of the seizures correlated with the level of Tau, such that less Tau meant lower spike frequencies and weaker seizures. This suggests that even moderately higher basal levels of Tau predispose neurons to hyperexcitability. Consequently, results from mice
Tau occurs in dendrites and postsynapses
In spite of its mainly axonal localization in adult neurons, a small fraction of Tau can move into dendritic spines in response to electrical stimulation [48]. There, the protein interacts with the actin cytoskeleton and may actively participate in the remodeling of spines which underlies synaptic plasticity. In pathological conditions, Aß (or other stressors) can trigger a substantial redistribution of Tau into dendrites and spines with harmful effects on synapses [49]. This missorting of Tau
Tau based treatment strategies and immunotherapy
In recent years, different treatment strategies of Tau-dependent pathology have been tested in transgenic Tau mice. This includes siRNA-mediated knock-down of P301S-Tau [51] or the application of Tau aggregation inhibitors. Examples are methylene blue (MB) or variants of it [52, 53, 54, 55]. In a clinical trial with mild/moderate AD patients MB showed significant treatment benefits [55] although a lack of dose–response was reported [56]. Another approach, indirectly related to Tau, is the
Conclusions
Beside Tau's main function in stabilizing microtubules for axonal transport, a variety of novel functions for neurons and glia have emerged recently. Tau regulates the susceptibility to hyperexcitation and at least one form of plasticity. Both human and mouse studies implicate soluble species of Tau, rather than insoluble aggregates, as more detrimental to proper neuronal function. Tau is not exclusively intracellular; instead Tau can be released into the extracellular space where it can be
Conflict of interest
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgement
We thank Eckhard Mandelkow for stimulating discussions during the preparation of this manuscript. The work was funded by DZNE and MPG.
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