Xiao Y, Wei L, Su J, Lei H, Sun F, Li M, Li S, Wang X, Zheng J, Wang JZ. A tau dephosphorylation-targeting chimeraselectively recruits protein phosphatase-1 to ameliorate Alzheimer's disease and tauopathies. Cell Chem Biol. 2024 Oct 17;31(10):1787-1799.e6. Epub 2024 Sep 30 PubMed.
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Laboratory for Alzheimer Disease
The propagation of neurofibrillary tangles (NFTs) from the entorhinal cortex to the limbic system and neocortex is known to correlate with cognitive decline due to accompanying neuronal loss. Tau, which constitutes NFTs, is excessively phosphorylated, and attempts have been made to inhibit this by blocking the kinase GSK-3β or by activating phosphatases. However, these approaches have not succeeded as treatments for dementia. The issue lies in the fact that kinases that phosphorylate tau or phosphatases that dephosphorylate it have many substrates other than tau; inhibiting or activating these can affect many cellular functions and potentially cause adverse side effects.
In this paper, Xiao et al. successfully used the D20 peptide to recruit protein phosphatase 1 (PP1) and specifically dephosphorylate tau molecules, ingeniously solving the problem of side effects by conferring tau specificity to PP1. The next question might be whether excessive phosphorylation is the cause or result of NFT formation.
At least our results indicate that phosphorylation at microtubule-binding sites S262 and S356 causes tau to dissociate from microtubules and form droplets through liquid-liquid phase separation (Soeda et al., 2024). On the other hand, when these sites are dephosphorylated and tau binds to microtubules, aggregated tau becomes aggresome-like and seems to be transported to protein degradation systems; thus, excessive phosphorylation of tau may indeed be a cause of NFTs and associated dementia. To date, therapies targeting tau have not been successful in clinical trials, in contrast to those targeting Aβ. Starting with Xiao et al.'s findings, we hope for the development of new therapeutic methods targeting tau.
References:
Soeda Y, Yoshimura H, Bannai H, Koike R, Takashima A. Intracellular Tau Fragment Droplets Serve as Seeds for Tau Fibrils. 2023 Sep 11 10.1101/2023.09.10.557018 (version 1) bioRxiv.
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