A team co-led by UCL researchers has reversed Alzheimer's disease pathology in mice using nanoparticles that help the brain to clear away toxic amyloid proteins naturally.
Unlike traditional nanomedicine, which relies on nanoparticles as carriers for therapeutic molecules, the approach utilised nanoparticles that are bioactive in their own right, known as "supramolecular drugs". The work has been published in the journal Signal Transduction and Targeted Therapy.
Instead of targeting neurons directly, the therapy restores the proper function of the blood-brain barrier, the vascular gatekeeper that regulates the brain's environment. By repairing this critical interface, the researchers achieved a reversal of Alzheimer's pathology in animals.
The brain obtains its energy from a vast blood supply, supported by a unique and dense vascular system, where a single capillary nourishes each neuron.
The brain contains approximately one billion capillaries, highlighting the vital role of brain vasculature in maintaining health and combating disease. These findings highlight the crucial role of vascular health, especially in diseases like dementia and Alzheimer's, where a compromised vascular system is closely linked.
The blood-brain barrier is a cellular and physiological barrier that separates the brain from the blood flow, protecting it from external dangers such as pathogens or toxins.
The team demonstrated that targeting a specific mechanism enables undesirable "waste proteins" produced in the brain to pass through this barrier and be eliminated in the blood flow. In Alzheimer's disease, the main "waste" protein is amyloid beta (amyloid-β, or Aβ), whose accumulation impairs the normal functioning of the neurons.
Researchers used mice that are genetically programmed to produce larger amounts of Aβ protein and develop a significant cognitive decline mimicking Alzheimer's pathology. They administered only three doses of the supramolecular drugs and afterward regularly monitored the evolution of the disease.
Dr Junyang Chen, first co-author of the study based at the West China Hospital of Sichuan University, who was a PhD student at UCL Chemistry during the work, said: "Only one hour after the injection, we observed a reduction of 50-60% in Aβ amount inside the brain."
The most striking data were the therapeutic effects. Researchers conducted various experiments to analyse the behaviour of the animals and measure their memory decline over several months, covering all stages of the disease.
In one of the experiments, they treated a 12-month-old mouse (roughly equivalent to a 60-year-old human) with the nanoparticles and found that six months later it had recovered the behaviour of a healthy mouse.
Study leader Professor Giuseppe Battaglia, formerly a professor at UCL Chemistry and now a UCL visiting professor, based at the Catalan Institution for Research and Advanced Studies (ICREA) and the Institute for Bioengineering of Catalonia (IBEC), said: "The long-term effect comes from restoring the brain's vasculature. We believe it works like a cascade: when toxic species, such as amyloid-beta (Aβ), accumulate, the disease progresses. However, once the vasculature can function again, it begins to clear Aβ and other harmful molecules, allowing the entire system to regain its balance.
"What's remarkable is that our nanoparticles act as a drug and seem to activate a feedback mechanism that brings this clearance pathway back to normal levels."
Amyloid-β clearance from the brain
In Alzheimer's disease, one of the key problems is that the brain's natural clearance system for toxic proteins like amyloid-β stops working properly.
Normally, the protein LRP1 acts as a molecular gatekeeper: it recognizes Aβ, binds to it through ligands (substances that help to form bonds), and ferries it across the blood-brain barrier into the bloodstream, where it can be removed. But this system is fragile. If LRP1 binds too much Aβ too tightly, the transport clogs and the LRP1 protein itself gets degraded inside the brain barrier cells, leaving fewer LRP1 "carriers" available.
On the other hand, if it binds too little, the signal is too weak to trigger transport. In both cases, the result is the same: Aβ builds up inside the brain.
The supramolecular drugs developed in this work act like a switch that resets the system. By mimicking the ligands of LRP1, they can bind to Aβ, cross the blood-brain barrier, and initiate the process of removing harmful proteins from the brain. In doing so, they help restore the vasculature's natural role as a waste-clearing pathway and bring it back to proper function.
Nanoparticles to treat Alzheimer's
In this study, the researchers introduce nanoparticles that act as supramolecular drugs, therapeutic agents in their own right rather than carriers of medication.
Designed with a bottom-up molecular engineering approach, these nanoparticles combine precise size control with a defined number of surface ligands, creating a platform able to interact with multiple cellular receptors in a highly specific way. By engaging receptor trafficking at the cell membrane, they open up a unique and novel way to regulate receptor function.
This precision not only enables the effective clearance of amyloid-β from the brain but also restores balance to the vascular system that maintains healthy brain function.
This therapeutic approach offers a promising pathway for developing effective clinical interventions, addressing vascular contributions to Alzheimer's disease, and ultimately enhancing patient outcomes.
Professor Lorena Ruiz Perez, based at IBEC and the University of Barcelona (UB), said: "Our study demonstrated remarkable efficacy in achieving rapid Aβ clearance, restoring healthy function in the blood-brain barrier and leading to a striking reversal of Alzheimer's pathology."
The study was a collaboration among researchers at UCL, IBEC, West China Hospital of Sichuan University, West China Xiamen Hospital of Sichuan University, the Xiamen Key Laboratory of Psychoradiology and Neuromodulation, University of Barcelona and the Chinese Academy of Medical Sciences.
