Review - Part of the Special Issue: Alzheimer's Disease - Amyloid, Tau and BeyondNew perspectives on the role of tau in Alzheimer's disease. Implications for therapy☆
Graphical abstract
Introduction
Tau protein is a microtubule-associated protein (MAP) that under physiological conditions regulates microtubules (MT) assembly, dynamic behavior, and spatial organization [1], [2]. More recently, tau has been shown to regulate the axonal transport of organelles, including mitochondria [3]. Tau is encoded by a single gene from which six major isoforms are expressed in adult brain through alternative splicing [4], [5]. The interaction between tau and tubulin is mediated by four imperfect repeat domains (encompassing 31–32 residues) encoded by exons 9–12 [6]. Alternative splicing of exon 10 results in the production of isoforms containing 3 or 4 binding domains (3R and 4R tau) [5]. Adult human brain contains equal amounts of 3R and 4R isoforms whereas foetal brain, however, only expresses 3R tau, demonstrating developmental regulation of exon 10 splicing [7]. Different brain regions also differ in the relative levels of 3R and 4R isoforms with granule cells in the hippocampal formation reported to have only 3R tau [5].
Within neurons, tau is predominantly found in axons [8] as a highly soluble phosphoprotein [9]. Phosphorylation is also developmentally regulated, with a high tau phosphorylation level during embryogenesis and early development, when only the shortest of the isoforms is being expressed. By contrast, adult brain expresses all six isoforms with relatively reduced phosphorylation levels compared with the foetal one (see [10] for a review).
A number of neurodegenerative disorders, including Alzheimer's disease (AD), present prominent tau pathology in the CNS, collectively referred to as tauopathies [11], [12], [13], [14], [15]. In tauopathies, the natively unfolded tau protein forms intracellular fibrillar structures of aggregated, hyperphosphorylated, and ubiquinated tau, which are associated with synaptic and neuronal loss. Upon abnormal phosphorylation, the microtubule-associated protein tau reduces its affinity for and dissociates from microtubules[15], [16], [17] In Alzheimer's disease (AD) brains tau accumulates in the neuronal perikarya and processes as paired helical filaments (PHF) [18], [19]. It has been suggested that at the single-cell level the defects start with a modification of tau by phosphorylation, resulting in a destabilization of microtubules giving rise to a “pre-tangle” stage [20]. After this stage, the destabilization of microtubules leads to loss of dendritic microtubules and synapses, plasma membrane degeneration, and eventually cell death [21].
The occurrence of fibrillar tau inclusions in tauopathies strongly supports a key role in the observed clinical symptoms and pathology. As a matter of fact, tau pathology in AD correlates better than amyloid-β (Aβ) pathology with the cognitive impairment observed in patients [22]. Furthermore, the discovery of mutations within the tau gene that cause a disease known as fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) [23], demonstrated that tau dysfunction, in the absence of amyloid pathology (as occurs in AD), was sufficient to cause neuronal loss and clinical dementia. Interestingly, tau is needed for Aβ to cause its toxicity both in vitro and in vivo, as suggested by the resistance shown by primary cultured neurons from tau knockout mice when exposed to Aβ [24] as well as by the rescuing premature mortality and preventing memory deficits observed in APP transgenic mice when crossed with tau knockout mice [25]. This supports a central role of tau in mediating Aβ toxicity in the early pathogenesis of AD.
Taken together, there is a large body of evidence clearly pointing out to a central role for tau in the pathogenesis of several neurodegenerative conditions including AD, laying the groundwork for its use as a target for the development of novel disease modifying therapeutics [26]. Drug discovery and development efforts for AD in the last two decades have primarily focused on targets defined by the amyloid cascade hypothesis, so far with disappointing results. In contrast, despite the fact that the presence of extensive tau pathology is central to the disease, tau-based strategies have received little attention until recently [27].
Section snippets
Tau-induced neurodegeneration
The knowledge accumulated in recent years strongly suggest that tau-induced neurodegeneration is most likely a consequence of a combination of loss of (tau) function as well as gain of (toxic) functions. On one hand, tau detachment from microtubules after hyperphosphorylation (or mutations) causes impaired microtubule function and axonal transport and eventually synaptic dysfunction and neuronal loss [28]. On the other hand, hyperphosphorylated tau molecules tend to self-assemble into filaments
Modulating tau phosphorylation
Although it is still debated whether phosphorylation of tau drives aggregation, or is a consequence of it, the strong correlation that exists between phosphorylation and tau pathology has laid the foundation to look for tau kinase inhibitors as potential therapeutics. However, there is not a single but multiple kinases involved in generating hyperphosphorylated tau in vivo [10], raising the issue of whether targeting specific kinases or distinct groups of kinases will be more effective in
Microtubule stabilization
Based on the notion that tau detachment from microtubules results in loss of its normal microtubule stabilizing function, most likely leading to axonal transport impairment and eventually to synaptic dysfunction, some microtubule-stabilizing agents have also been proposed as a therapeutic alternative. Among those, some anti-mitotic compounds such as paclitaxel or epothilone have been used in tau transgenic animals (reviewed in [49]). The most advanced of these agents is davunetide (NAP), an
Inhibiting tau aggregation
Another potential point of therapeutic intervention is the aggregation process itself in which a variety of different tau species are formed: monomers, oligomers, prefilaments, truncated, granules, fibrils, insoluble aggregates. As discussed above, some sort of hyperphosphorylated, misfolded soluble tau intermediates are the actual (or the most) toxic tau species, so that inhibiting early aggregation steps might be critical for a successful pharmacological intervention aimed at preventing
Reducing tau levels
It has been over twenty years that increased intracellular tau levels were described in brains from AD patients as compared to age-matched non-demented controls [58] and it has thus been suggested that increased tau levels might be toxic for neurons. On the other hand, several tau-deficient mouse strains have been generated [61], [62], [63], [64], [65], [66], [67] and while initially reported to lack an overt phenotype, behavioral changes and motor deficits have been reported recently in some
Decreasing extracellular tau
Development of tau pathology is associated with progressive neuronal loss and cognitive decline. In the brains of AD patients, tau pathology spreads following a predictable, anatomically defined progression pattern, which has suggested that the actual interneuronal transfer of a toxic factor must be involved in the progression of neurodegenerative tauopathies [84], [85]. Although traditionally thought of as an exclusively intracellular protein and its presence in the extracellular milieu (or in
Immunotherapy targeting tau
Immunotherapy for various neurodegenerative diseases have recently emerged as a promising approach for the clearance of pathological proteins in these disorders [100]. The disappointing outcome of several amyloid-based pharmacological approaches, including anti-amyloid immunotherapy, in late stage clinical trials during the last few years has spurred increased interest in novel tau-based therapies and various vaccination approaches have been recently assessed in preclinical models for
Future developments
Drug discovery and development efforts for AD in the last two decades have primarily focused on targets defined by the amyloid cascade hypothesis, so far with disappointing results. In contrast, tau-based strategies have received little attention until recently despite that the presence of extensive tau pathology is central to the disease. However, as discussed in this review, a number of different strategies targeting several aspects of the tau pathogenesis are being actively pursued,
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Chemical compounds studied in this article: Tideglusib (PubChem CIP: 11313622); Davunetide (PubChem CIP: 9832404); Lithium chloride (PubChem CIP: 433294); Lithium carbonate (PubChem CIP: 11125); Methylene blue (PubChem CIP: 6099); Leucomethylene blue (PubChem CIP: 164695); Sodium selenate (PubChem CIP: 25960); S-AMPA (PubChem CIP: 158397); Divalproex (PubChem CIP: 23663956).