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

Abstract

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.

Fig. 1.. Tau isoforms and posttranslational modifications.

(A) Six major isoforms of tau are produced in brain from the MAPT gene through alternative splicing. N1 and N2 denote N-terminal inserts; R1 to R4 indicate microtubule-binding repeat domains, whose differential inclusion results in the generation of 3R versus 4R tau. Noncoding exons are shown in white; coding exons not expressed in brains or humans are in light grey; coding exons in human brain are in light blue. aa, amino acids. (B) Physiological posttranslational modifications identified by mass spectrometry of tau isolated from brain tissues of healthy adult WT mice. Note that some amino acid modifications could compete with each other (e.g., ubiquitination and acetylation). K, Lys; R, Arg; S, Ser; T, Thr; and Y, Tyr. [Adapted from figure 1a of (9)]

Fig. 2.. Physiological but disease-enabling functions of tau.

(A) Simplified conceptual diagram highlighting how targeting tau could block the development or progression of disease, even when tau is neither a driver nor a direct mediator of the pathogenic cascade. (B) Tau regulates interactions among the tyrosine kinase Fyn, N-methyl-D aspartate receptors (NMDARs), and postsynaptic density protein 95 (PSD-95) (44), as well as between PSD-95 and synaptic Ras GTPase-activating protein 1 (SynGAP1), which negatively regulates synaptic extracellular signal-regulated kinase (ERK) activation (20). Although these tau activities may normally form part of the complex network of regulators that support synaptic and neuronal activities, they may also allow pathological overstimulation of glutamate receptors to result in “excitotoxicity,” a process tau reduction has been shown to counteract (4, 20). P, phosphorylation; MEK, mitogen-activated protein kinase kinase. [Adapted from figure 3 of (4) with permission from Elsevier] (C and D) In mouse models, the presence of endogenous WT tau allows other processes to overactivate the PI3K-Akt-mTOR signaling pathway, which in turn promotes the development of autism-like behaviors, including excessive stereotypic movements, social interaction deficits and cognitive inflexibility (18). (C) Partial or complete genetic reduction of tau prevented excessive stereotypic movements (time spent engaged in such movements in seconds) in Scn1a^RX/+ knockin mice, which carry a sodium channel mutation that causes autism and epilepsy in humans. By contrast, tau reduction did not alter this behavior in mice without this mutation. Numbers of mice per group are indicated in bars. ****P < 0.0001 vs. WT (Scn1a^+/+Mapt^+/+) controls or as indicated by brackets [two-way analysis of variance (ANOVA) with Holm-Sidak test]. ns, not significant. Error bars indicate SEM. [Reprinted from figure 1A of (18) with permission from Elsevier] (D) Because PTEN counteracts PI3K, tau’s ability to inhibit PTEN activation (46) may enable normal activity of the PI3K-Akt-mTOR pathway under physiological conditions. However, when pathological processes overactivate PI3K, as in some autism spectrum disorders, tau’s constraint of PTEN becomes maladaptive and allows for overactivation of the downstream signaling cascade, promoting the development of autism symptoms through diverse anatomical and pathophysiological mechanisms. Tau reduction counteracts this process by releasing the activity of PTEN and possibly also by blocking neural network dysfunctions. PIP2, phosphatidylinositol 4,5-biphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; TSC1/2, tuberous sclerosis 1 and 2; S6, ribosomal protein S6; ASD, autism spectrum disorder. [Reprinted from figure 3 of (18) with permission from Elsevier]

Fig. 3.. Tau-focused therapeutic strategies.

Approaches that target the upstream components (bold) of the depicted cascade may have the greatest therapeutic potential because the downstream components fan out into a variety of potential targets whose relative pathogenic impacts are uncertain.

Fig. 4.. Tau-related challenges and needs.

In principle, several of the trailblazing discoveries reviewed here could lead to the development of better treatments for AD and other tauopathies. However, many efforts to develop treatments for brain diseases have failed, in large part because of an inadequate understanding of the pathobiology of these complex disorders and, perhaps, because too many fundamental knowledge gaps, alternative interpretations of data, and methodological complexities did not receive the attention they deserved. Addressing the scientific knowledge gaps and technological challenges highlighted in this Review could accelerate and enable the development of truly impactful tau-related diagnostics and therapeutics. PTM, posttranslational modification.