Tau neurotoxicity and rescue in animal models of human Tauopathies

doi:10.1016/j.conb.2015.09.004

Current Opinion in Neurobiology

Volume 36, February 2016, Pages 52-58

https://doi.org/10.1016/j.conb.2015.09.004 Get rights and content

Highlights

•
Soluble species of Tau, rather than aggregates, are more detrimental to proper neuronal function.
•
Tau is released from synaptic terminals into the extracellular space.
•
Tau plays a role in controlling susceptibility to hyperexcitation.
•
Tau based antibody or aggregation inhibitor treatment is beneficial in murine Tauopathy models.

Pathological Tau is a hallmark of various neuronal disorders and spreads in the brain of Alzheimer patients in a well-defined manner. 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 plays a role in neuron-glia contact formation. Studies implicate soluble oligomeric 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. This has led to the hypothesis of a prion-disease like mechanism to explain the stereotypical progression of Tau. Targeting pathological Tau with antibodies or aggregation inhibitors may help to prevent pathology.

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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Tauopathies are a family of neurodegenerative diseases characterized by the presence of abnormally hyperphosphorylated Tau protein. Several studies have proposed that increased extracellular Tau (eTau) leads to the spread of cerebral tauopathy. However, the molecular mechanisms underlying eTau-induced neurotoxicity remain unclear. Previous in vitro studies reported that the ecto-enzyme tissue-nonspecific alkaline phosphatase (TNAP) dephosphorylate eTau at different sites increasing its neurotoxicity. Here, we confirm TNAP protein upregulation in the brains of Alzheimer's patients and found a similar TNAP increase in Pick's disease patients and P301S mice, a well-characterized mouse model of tauopathies. Interestingly, the conditional overexpression of TNAP causes intracellular Tau hyperphosphorylation and aggregation in cells neighbouring those overexpressing the ectoenzyme. Conversely, the genetic disruption of TNAP reduced the dephosphorylation of eTau and decreased neuronal hyperactivity, brain atrophy, and hippocampal neuronal death in P301S mice. TNAP haploinsufficiency in P301S mice prevents the decreased anxiety-like behaviour, motor deficiency, and increased memory capacity and life expectancy. Similar results were observed by the in vivo pharmacological blunting of TNAP activity. This study provides the first in vivo evidence demonstrating that raised TNAP activity is critical for Tau-induced neurotoxicity and suggest that TNAP blockade may be a novel and efficient therapy to treat tauopathies.
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View full text

Tau neurotoxicity and rescue in animal models of human Tauopathies

Highlights

Introduction

Section snippets

Soluble oligomeric forms of Tau can be toxic

Tau oligomers impair cognition in humans

Transmission of Tauopathy

Tau is released from living cells

Prion-like mechanism of spreading

Pathological Tau reduces network activity

Endogenous Tau regulates hyperexcitability

Tau occurs in dendrites and postsynapses

Tau based treatment strategies and immunotherapy

Conclusions

Conflict of interest

References and recommended reading

Acknowledgement

Acta Neuropathol

J Neurosci

J Neurochem

Ann Clin Transl Neurol

Acta Neuropathol Commun

Ann Neurol

Philos Trans R Soc Lond B Biol Sci

Curr Gene Ther

Exp Neurol

J Biol Chem

EMBO Mol Med

J Biol Chem

A protein factor essential for microtubule assembly

Proc Natl Acad Sci U S A

The distribution of tau in the mammalian central nervous system

J Cell Biol

MAP2 and tau segregate into dendritic and axonal domains after the elaboration of morphologically distinct neurites: an immunocytochemical study of cultured rat cerebrum

J Neurosci

Biochemistry and cell biology of tau protein in neurofibrillary degeneration

Cold Spring Harb Perspect Med

Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model

Science

Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy

J Neurosci

Antisense reduction of tau in adult mice protects against seizures

J Neurosci

Tau reduction diminishes spatial learning and memory deficits after mild repetitive traumatic brain injury in mice

PLOS ONE

Soluble pathological tau in the entorhinal cortex leads to presynaptic deficits in an early Alzheimer's disease model

Acta Neuropathol

Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau

Acta Neuropathol

The intersection of amyloid beta and tau at synapses in Alzheimer's disease

Neuron

Alzheimer's pathogenesis: is there neuron-to-neuron propagation?

Acta Neuropathol

Brain homogenates from human tauopathies induce tau inclusions in mouse brain

Proc Natl Acad Sci U S A

Tau imaging: early progress and future directions

Lancet Neurol

Cerebrospinal fluid biomarkers in trials for Alzheimer and Parkinson diseases

Nat Rev Neurol

Tau suppression in a neurodegenerative mouse model improves memory function

Science

Electrophysiological changes precede morphological changes to frontal cortical pyramidal neurons in the rTg4510 mouse model of progressive tauopathy

Acta Neuropathol

Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology

Brain

Cellular, synaptic, and biochemical features of resilient cognition in Alzheimer's disease

Neurobiol Aging

Prefibrillar tau oligomers in mild cognitive impairment and Alzheimer's disease

Neurodegener Dis

Accumulation of tau induced in neurites by microglial proinflammatory mediators

FASEB J

Proteopathic tau seeding predicts tauopathy in vivo

Proc Natl Acad Sci U S A

Research in motion: the enigma of Parkinson's disease pathology spread

Nat Rev Neurosci

Propagation of tau pathology in a model of early Alzheimer's disease

Neuron

Trans-synaptic spread of tau pathology in vivo

PLoS ONE