**6.2 Therapies targeting tau PTMs**

Acetylation at specific sites of tau is shown to inhibit the degradation of hyperphosphorylated tau, obstruct synaptic plasticity and promote cognitive impairment in AD mouse models [91]. Salsalate, a non-acetylated dimer of salicylic acid commonly used as a non-steroidal anti-inflammatory drug, can inhibit acetyltransferase p300-induced tau acetylation, thus enhancing tau turnover and reducing tau levels [145]. O-GlcNAcylation negatively regulates tau phosphorylation by competing for the phosphorylation sites [146]. Two small molecular inhibitors of O-GlycNAcase (LY3372689 and ASN51) are currently undergoing clinical trials.

Hyperphosphorylation is the crucial PTM that determines the propagation of tau pathology. Inhibition of tau hyperphosphorylation has long been considered as a potential therapeutic strategy. Tau phosphorylation can be modulated by the balance between protein kinases and phosphatases. Nasal insulin and the GSK-3 inhibitor Lithium that inhibit tau phosphorylation via activating PI3K signaling, and PP2A activator Metformin aimed at tau dephosphorylation are currently under development or evaluation in clinical trials [122].

## **6.3 Other therapies**

Knockout of MAPT gene induces no obvious phenotype except for behavioral deficits in aged mice [147]. Reducing the levels of endogenous tau shows protection against cognitive impairments and behavioral abnormalities in AD mice [148]. BIIB080, the first antisense oligonucleotide (ASO) targeting the translation of tau mRNAs, has just started Phase 1 and Phase 2 clinical trials. Recently, a selective protein degradation approach achieved by the proteolysis targeting chimeras (PROTACs) is utilized to decrease tau protein in the brain [82, 149]. PROTACs form a ternary complex with the target protein and ubiquitin E3 ligase. E3 ubiquitin ligase stimulates polyubiquitination of the targets and facilitates its following recognition and degradation by the 26S proteasome [149]. PROTACs targeting tau remarkably decreased tau levels and improved synaptic and cognitive functions in wildtype and AD mice [150].

In the past few years, inhibitors of tau aggregation were considered as potential therapies for AD for their roles in preventing the prion-like seeding and propagation of tau pathology. Unfortunately, the clinical trials of corresponding small molecular drugs, such as methylene blue, Rember TM, and LMTX, did not show the expected effect and are thus discontinued. NPT088, a fusion protein consisting of human-IgG 1-Fc and an active fragment binds to and remodels misfolded aggregates of tau, also exhibited no effect on brain plaques, tau aggregates or AD symptoms [151].

What's more, the disruption of microtubules is one of the main consequences of tau-induced neurotoxicity. Therefore, stabilization of microtubules may also be a potential therapeutic approach associated with tau. However, the efficacy of microtubule stabilizers (e.g. TPI-287) in the treatment of AD still requires further evaluation.

### **7. Conclusions and perspectives**

In summary, tau-mediated microtubule dynamics and assembly play essential roles in neuronal transport and the maintenance of synaptic structure and function. In neurodegenerative diseases, tau undergoes a series of pathological changes, including mutation, abnormal alternative splicing, abnormal PTMs and prion-like seeding and propagation. Certain benefits of therapeutic approaches targeting

pathological tau have emerged in the treatment of AD and related tauopathies. Recently, proteomics results indicate significant heterogeneity of tau pathology in different patients, raising the possibility that personalized approaches according to the biochemical characteristics of tau may achieve better therapeutic effects [10]. It is also worth noting that tau interacts with other risk factors of neurodegenerative diseases, such as Aβ [152], apolipoprotein E [153], α-synuclein [154], metal dysregulation [155], defective mitophagy [156], stress and inflammation [157] and so on. Therefore, further investigation of the comprehensive map of tau interactions will better reveal the pathogenesis of neurodegenerative diseases.
