When a natural barrier in the brain stops working, Alzheimer’s finds fertile ground. A team of researchers used bioactive nanoparticles to restore this barrier and, in mice, reverse the disease. Result: a disappearance of amyloid plaques and a return to “normal” memory. This advance opens a new path: not acting directly on neurons, but repairing the brain’s “cleaning” system. A hope – still fragile – towards human therapies.
The role of the blood-brain barrier: the vital “cleaner” of the brain
The brain is not an isolated space with no connection to the rest of the body: it is protected by a very strict interface called the blood-brain barrier. This cellular structure regulates exchanges between the blood circulation and brain tissue, preventing toxins, pathogens or unwanted molecules from freely entering the brain. But it also allows the export of metabolic waste.
In the context of Alzheimer’s disease, this barrier becomes ineffective: toxic proteins, notably amyloid-β (Aβ), accumulate inside the brain (the famous amyloid plaques), because they cannot be eliminated correctly. The transport of Aβ relies in particular on a specific receptor, LRP1, which recognizes the molecule and transports it through the barrier into the circulation blood. However, if this system is saturated, damaged or dysfunctional, the “cleaning” stops.
Researchers in Barcelona and China designed a bold strategy: rather than targeting the neurons themselves, they sought to restore brain vascularization and the function of this barrier. It is this idea of “restoring the filter/cleaning system” — and not intervening only on the nerve cells — that really changes the perspective in the fight against Alzheimer’s.
Bioactive nanoparticles to restore the proper functioning of the barrier
The innovation of this study lies in the use of supramolecular nanoparticles, not as simple drug vectors, but as active agents capable of modulating cellular functioning.
These nanoparticles are designed to interact with the LRP1 receptor, mimicking its ligands, to promote the Aβ elimination system. The idea is to be able to bind to LRP1 without blocking transport but on the contrary by reactivating this natural cleansing process.
This nanoparticles were injected into animal models of Alzheimer’s disease, mice suffering from a neurological equivalent. And there, the result exceeded the expectations of the researchers. Junyang Chen says: “Just 1 hour after the injection, we observe a 50 to 60% reduction in the amount of Aβ inside the brain“.
This mechanism acts as a signal to restart the brain filter: the nanoparticles restart the cleaning flow.
Giuseppe Battaglia explains: “The long-term effect comes from the restoration of cerebral vascularization. What is remarkable is that our nanoparticles act like a drug and appear to activate a feedback mechanism that restores this clearance pathway to normal levels.”
Disappearance of amyloid plaques and cognitive recovery in mice
The results obtained are both spectacular and measured: in the animal model, the administration of only three doses was enough to trigger massive effects.
In the first few hours alone, a 45-60% reduction in Aβ levels is seen in the brain. At the same time, Aβ levels in blood plasma increase up to eight times, indicating the export of the molecule out of the brain.
© Institute for Bioengineering of Catalonia (IBEC)
Images of mouse brains taken under a fluorescence microscope after treatment (left) or not (right) with nanoparticles. In red, amyloid plaques. In green, the blood-brain barrier vessels.
Behaviorally, treated mice show better performance in spatial and memory tests, at a level comparable to healthy mice. These benefits last up to 6 months after treatment.
In a landmark experiment, a 12-month-old mouse (equivalent to a 60-year-old human) was followed for up to 18 months (90-year-old human equivalent). After treatment, she regained behavior almost identical to that of a non-diseased mouse.
These results show that the restoration of the blood-brain barrier seems to trigger a saving mechanism: better elimination of Aβ, which allows the neuronal environment to rebalance and recover its functions.
What concrete hope for man? From mouse brains to human challenges
The results are fascinating, but reversing Alzheimer’s disease in mice does not guarantee direct success in humans. Several steps remain to be taken.
- Toxicity, biocompatibility, safety : it will be necessary to demonstrate that these nanoparticles are harmless in the long term in humans, that they do not trigger inflammation or cerebral side effects. Nanoparticles are already being studied for Alzheimer’s, but their transition to humans poses rigorous safety challenges;
- Biological differences between mice and human brains : size, vascular density, barrier architecture, genetic variability — all of this makes transfer far from obvious. Dosage, distribution in the human brain, and precise targeting are major obstacles;
- Regulations, clinical trials, financing : even if the proof of concept is strong, conducting trials in humans requires rigorous protocols, preclinical and clinical phase trials, and colossal funding.
However, this experimental victory suggests a new therapeutic strategy against Alzheimer’s disease: not by focusing on neurons, but by restoring the vascular system and the “cleaning system” of the brain itself – a research option little exploited until now.
The road to humans will therefore be long – but for the first time, Alzheimer’s appears to be in decline, thanks to a new strategy.