Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β deposition and tau pathology. In AD, tau becomes abnormally phosphorylated, mislocalizes from axons, and forms insoluble aggregates that correlate closely with cognitive decline and disease progression across brain regions. Hyperphosphorylated tau (p-tau) has emerged as a promising target for disease-modifying therapy. However, systemic tau-targeted therapeutics are often hampered by insufficient brain exposure and off-lesion distribution.

In a study published in Journal of the American Chemical Society, a team led by YU Haijun from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences, along with XU Tianfeng from SIMM and XU Zhiai from East China Normal University, revealed a pathogenic cascade in which reduced protein phosphatase 2A (PP2A) activity promoted p-tau accumulation and activated microglia amplified p-tau propagation. They then developed a glycoengineered proteolysis-targeting chimera (PROTAC) prodrug nanoparticle platform for lesion-specific p-tau modulation.

The researchers first analyzed human brain samples, cell models, and mouse models of AD-related tau pathology, and observed reduced PP2A activity, increased p-tau burden, and microglia-associated p-tau spreading. They then designed a library of p-tau-targeting PROTACs, and identified PROTAC-7 as a lead compound. PROTAC-7 degraded multiple pathological p-tau species while largely sparing physiological tau.

To improve brain delivery and lesion-restricted activity, the researchers assembled glycoengineered PROTAC nanoparticles (GPtMP NPs). The NPs were constructed from galactose- and cyclodextrin-grafted polysialic acid, the microglial modulator PLX5622, and a reactive oxygen species (ROS)-sensitive conjugate of PROTAC-7 and memantine. Galactose promoted transport across the blood-brain barrier through a glucose transporter 1 (GLUT1)-related pathway. In ROS-rich AD lesions, thioketal linker was cleaved and released therapeutic payloads locally.

In okadaic acid (OA)-induced AD mouse model, P301S brain extract (P301SBE)-accelerated P301S tauopathy model, and the 3×Tg transgenic AD mouse model, the researchers found that GPtMP NPs achieved lesion-confined coordination of p-tau degradation, p-tau dephosphorylation, and blockade of microglia-mediated p-tau propagation. This strategy reduced tau pathology, restored synaptic function, and improved learning- and memory-related behavioral outcomes.

This work established a glycoengineered PROTAC nanoplatform for spatially confined p-tau degradation. It supports lesion-specific modulation of tau homeostasis as a potential disease-modifying strategy for AD.