Jul 2026· ACS Chemical Biology· Vol 21 8, pp.
1906-1916
· 0 citations· 49 references
Medicine
TL;DR
Results indicate that MB-2-VHL2 can reduce both total Tau and p-Tau levels in vivo, and support further optimization and preclinical evaluation of Tau-targeted PROTACs as a potential therapeutic strategy for AD.
Abstract
Tau aggregation and hyperphosphorylation are key pathological features of Alzheimer's disease (AD). Because Tau is intrinsically disordered, conventional small-molecule inhibitors have achieved limited success. Proteolysis-targeting chimeras (PROTACs) enable the targeted proteasomal degradation of previously considered undruggable proteins. We designed Tau-targeted PROTAC candidates using methylene blue (MB) as a recognition moiety for aggregation-prone motifs within the microtubule-binding region and varied the linker lengths and E3 ligase recruitment ligands to optimize degradation efficiency. Cell-based screening revealed that MB-2-VHL1 and MB-2-VHL2 are active degraders. In vivo studies confirmed a reduction in total Tau levels and degradation of phosphorylated Tau (p-Tau). In 3xTg-AD mice, subcutaneous administration of MB-2-VHL2 was associated with reduced hippocampal Tau and p-Tau levels and improved recognition memory and spatial learning. MB-2-VHL2 was also detectable in both serum and brain tissue by LC-MS/MS after subcutaneous administration and did not cause detectable histological or biochemical toxicity. These results indicate that MB-2-VHL2 can reduce both total Tau and p-Tau levels in vivo. Although the reduction in p-Tau appeared more pronounced under our experimental conditions, whether MB-2-VHL2 preferentially targets pathological Tau remains to be determined. Overall, these findings support further optimization and preclinical evaluation of Tau-targeted PROTACs as a potential therapeutic strategy for AD.
This dissertation explores the hypothesis that G4-forming nucleic acids represent a mechanistic link between cellular stress, RNA biology, and tau aggregation in AD and establishes G-quadruplexes as previously underappreciated regulators of tau biology and implicates RNA structure as an active contributor to AD pathogenesis.
Alzheimer's disease (AD) is the most dominant form of dementia characterized by neurodegeneration which leads to progressive cognitive decline and memory loss, the common symptoms of AD. While amyloid-β peptide accumulation has traditionally been the primary focus of AD research, there is growing evidence that tau pathology also contributes significantly in disease progression. Tau is a microtubule-associated protein that normally stabilizes microtubules and supports axonal transport within neurons. However, abnormal hyperphosphorylation causes tau to detach from microtubules, misfold and aggregate into toxic filaments which ultimately lead to neurodegeneration and eventually cell death. This paper reviews the structure of tau protein, its physiological and pathological behaviours and tau's mechanism in terms of disease progression. This paper also examines clinical and preclinical evidences and discusses the efficacy and limitations of three tau-targeted therapeutic approaches: gosuranemab, a monoclonal antibody designed to prevent the spread of extracellular tau; BIIB080, an antisense oligonucleotide that reduces tau production by targeting MAPT mRNA; and leucomethylthioninium bis (LMTM), a tau aggregation inhibitor. Studies also suggest the potential of combination therapies targeting multiple pathological pathways to enhance efficacy. Though no tau-targeted therapy has yet to demonstrate definitive clinical benefit, continued research supports tau as an important therapeutic target and contributes to the development of more effective treatments for AD.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and memory loss, resulting from various pathological processes such as amyloid-β aggregation, tau hyperphosphorylation, oxidative stress, cholinergic dysfunction, and metal ion imbalance. Current treatments, like acetylcholinesterase inhibitors and NMDA receptor antagonists, only help with the symptoms and don't change how the disease gets worse. The fact that AD has many causes shows how important it is to come up with new ways to treat it. Multi-target directed ligands (MTDLs) have become a promising approach in the last few years. They are meant to work on several important molecular targets that are thought to play a role in the development of Alzheimer's disease. This review summarises progress in the creation and design of MTDLs. It talks about hybrid molecules (like tacrine–chromene derivatives), peptide-based scaffolds, flavonoid conjugates, dual GSK-3β/tau aggregation inhibitors, and new PDE- and AChE-targeting compounds. Compared to regular polypharmacy, MTDLs have more benefits, such as better effectiveness, less toxicity, better compliance, and better pharmacological profiles. Recent advances in medicinal chemistry and structure-based design bolster the argument for MTDLs as next-generation therapeutic candidates, notwithstanding challenges like bioavailability and blood–brain barrier penetration. Ongoing enhancement of these compounds may eventually yield disease-modifying therapies that can impede or avert the advancement of Alzheimer's disease.
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In this study, molecular-level insights are provided into the interaction mechanisms of γ-secretase inhibitors, contributing to a better understanding of structure-energy relationships that are essential for the rational design of more selective and effective therapeutic agents for Alzheimers disease.
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