Tau: Enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies

The many faces of tau The protein tau is implicated in several brain disorders, including Alzheimer's disease, suggesting that it could be a target of therapeutics. However, because it is unclear how the pleiotropic roles of tau lead to neural pathology in different brain diseases, drug development remains challenging. Chang et al. review the possible mechanisms of tau in brain diseases and possible paths forward to improving research and drug development. Science, this issue p. eabb8255 BACKGROUND The microtubule-associated protein tau has been implicated in the pathogenesis of Alzheimer’s disease and a range of other neurodegenerative disorders (called “tauopathies”). As the number of people with tauopathies is rising in aging populations across the world, interest in the fundamental biology of this protein and in the development of tau-targeting treatments has been expanding rapidly. Recent insights into the complexity of this intrinsically disordered protein suggest that tau is a worthy but challenging target whose multifaceted nature will likely require a multipronged therapeutic approach. Derived from a single gene by alternative splicing, six major isoforms of tau have been identified in the human brain. In addition, tau is subject to many different posttranslational modifications, further indicating that it may be regulated by multiple processes and may participate in diverse functions. ADVANCES Tau is widely presumed to stabilize microtubules. However, the experimental reduction or ablation of tau in vivo does not alter many neural properties and processes that likely depend on microtubules, including neuronal integrity, axonal transport, synapse formation, and complex brain functions. Although tau reduction seems to have minimal effects on otherwise unmanipulated brains, it can prevent or diminish aberrant cell signaling, neural network dysfunctions (e.g., epileptic activity), and behavioral alterations caused by diverse disease processes, which suggests that tau activities are needed for other pathogenic triggers to cause these derangements. In addition to this “enabling bystander” role, tau’s interactions with a large number of other proteins can cause adverse gains of function, which are associated with—and possibly caused by—the formation of abnormal tau structures and assemblies. Because abnormal forms of tau trigger a plethora of pathomechanisms, targeting individual downstream mechanisms may have limited therapeutic impact, unless the relative pathogenic importance of the specific mechanism has been well established in experimental models that allow for conclusive validation of cause-and-effect relationships. Although much attention has focused on the abnormal aggregation of tau in tauopathies and on the ability of tau “seeds” to spread from neuron to neuron, internalization of propagating tau does not appear to impair neuronal survival or brain functions. Moreover, tau reduction prevents or diminishes neural network dysfunction and behavioral abnormalities also in disease models that do not have abnormal tau inclusions, which suggests that there is more to tau than aggregation and propagation. A promising diversification of tau-targeting therapeutic strategies is beginning to address this complexity. Lowering overall tau levels may have the greatest potential, as this strategy bypasses the unresolved questions of which forms of tau and which downstream mechanisms are most detrimental in any given condition. OUTLOOK Many efforts to develop better treatments for neurodegenerative diseases have failed, in large part because of an inadequate understanding of disease mechanisms and, perhaps, because too many fundamental knowledge gaps, alternative interpretations of data, and methodological complexities did not receive the attention they deserved. This Review highlights important gaps in the understanding of tau and the methodological advances needed to fill them. It also pinpoints obstacles that could complicate the translation of tau-related scientific discoveries into better therapeutics and offers pragmatic strategies to overcome these challenges. Despite the extraordinary progress that has been made to date, the main physiological functions that tau fulfills in the adult and aging brain remain to be defined. Another critical objective is to develop better experimental models and technologies to rigorously compare different tau species and pathomechanisms, particularly their relative impacts on neuronal functions and survival in vivo. For the development of truly informative biomarkers and effective therapeutics, it will be critical to rigorously differentiate between associations and cause-and-effect relationships. Until the main drivers of neuronal dysfunction and demise have been identified for Alzheimer’s disease and other conditions in which tau has a causal or enabling role, it seems prudent to focus on pragmatic strategies, such as overall tau reduction, while also expanding efforts to further validate the importance of more-specific targets and approaches. Investigational approaches to lower overall tau levels include tau-targeting antisense oligonucleotides, which have advanced into a clinical trial for early Alzheimer’s disease, and the development of small-molecule drugs that can modulate the production or degradation of tau. The most desirable tau-targeting therapeutics would be efficacious across diverse tauopathies, as well as affordable, easy to access, and well tolerated when administered over long periods of time to fragile groups of people who likely take multiple other medications. Potential tau pathomechanisms. Developing effective tau-targeting therapeutics will require a better understanding of how exactly tau contributes to Alzheimer’s disease and other disorders of the central nervous system. Potential mechanisms likely fall into the three broad categories shown. However, the relative pathogenic impact and overall importance of individual mechanisms have yet to be defined in truly disease-relevant contexts and may differ among diseases and even patients. The blue box on the right indicates tau activities that do not directly mediate but indirectly promote or facilitate pathogenic processes. Several lines of evidence implicate the protein tau in the pathogenesis of multiple brain disorders, including Alzheimer’s disease, other neurodegenerative conditions, autism, and epilepsy. Tau is abundant in neurons and interacts with microtubules, but its main functions in the brain remain to be defined. These functions may involve the regulation of signaling pathways relevant to diverse biological processes. Informative disease models have revealed a plethora of abnormal tau species and mechanisms that might contribute to neuronal dysfunction and loss, but the relative importance of their respective contributions is uncertain. This knowledge gap poses major obstacles to the development of truly impactful therapeutic strategies. The current expansion and intensification of efforts to translate mechanistic insights into tau-related therapeutics should address this issue and could deliver better treatments for a host of devastating conditions.