Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β deposition and tau pathology. Physiological tau stabilizes microtubules and supports axonal transport and synaptic plasticity. 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 therefore 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.

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

The team first combined analyses of human brain samples, cell models, and mouse models of AD-related tau pathology. They observed reduced PP2A activity, increased p-tau burden, and microglia-associated p-tau spreading. The researchers 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 team further assembled glycoengineered PROTAC nanoparticles (GPtMP NPs). The nanoparticles were constructed from galactose- and cyclodextrin-grafted polysialic acid, the microglial modulator PLX5622 (PLX), and a reactive oxygen species (ROS)-sensitive conjugate of PROTAC-7 and memantine. Galactose promoted transport across the blood-brain barrier (BBB) through a glucose transporter 1 (GLUT1)-related pathway. In ROS-rich AD lesions, the thioketal linker was cleaved and released therapeutic payloads locally.

In the okadaic acid (OA)-induced AD mouse model, the P301S brain extract (P301SBE)-accelerated P301S tauopathy model, and the 3×Tg transgenic AD mouse model, 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 also supported lesion-specific modulation of tau homeostasis as a potential disease-modifying strategy for AD.

Schematic illustration of glycoengineered PROTAC nanoparticles that cross the BBB and release therapeutic payloads in ROS-rich AD lesions for coordinated p-tau degradation, dephosphorylation, and propagation blockade (Image by YU Haijun’s group)

DOI: 10.1021/jacs.6c05275

Link: https://doi.org/10.1021/jacs.6c05275

Keywords: Alzheimer’s disease; hyperphosphorylated tau; lesion-specific protein degradation

Contact:

DIAO Wentong

Shanghai Institute of Materia Medica

E-mail: diaowentong@simm.ac.cn