Novel strategies for targeting tau oligomers in neurodegenerative diseases

Tau protein is a soluble microtubule-associated protein enriched in neurons, is mainly distributed in the central nervous system, and is responsible for stabilizing neurons. Tau maintains nerve cell morphology and internal transport by binding to normal microtubules. In neurodegenerative diseases, such as Alzheimer's disease (AD), tau proteins undergo aberrant phosphorylation, resulting in their removal from microtubules and the formation of neurofibrillary tangles (NFTs), which are key pathological features. In contrast to the late formation of non-soluble NFTs, early, smaller, soluble tau oligomers (tauO) with disseminated toxicity are considered necessary in neurodegenerative disorders, such as the primary form of tau toxicity in the AD process. Although an increasing number of studies are focusing on tauO, there are still problems to be solved, mainly concerning the molecular and inhibitory mechanisms of tauO toxicity. In this paper, we summarize the new strategies for the molecular mechanisms of tauO toxicity, detection methods, and interventions in the last five years. An outlook on these new strategies and the challenges that may be foreseen is presented to provide new directions for future applications in the clinical treatment of neurodegenerative diseases.