Alzheimer's affects more than 50 million people worldwide today, and no cure is available. Despite decades of research, clinical trials directly targeting neurons or amyloid plaques have produced modest results. However, a new avenue is emerging: the central role of the blood-brain barrier, this biological filter which protects the brain, but becomes dysfunctional in the disease.
Rethinking Alzheimer’s through the blood-brain barrier
For a long time, Alzheimer's research focused on neurons, particularly on amyloid-β (Aβ) protein deposits in brain tissue. But this approach often failed to reverse symptoms. An international team proposes a paradigm shift: targeting the blood-brain barrier (BBB), an essential cellular filter that controls exchanges between the blood and the brain.
The BBB constitutes a very dense and selective structure, formed mainly of endothelial cells. It prevents toxins and pathogens from reaching the brain, while allowing necessary nutrients to pass through. In Alzheimer's disease, this barrier becomes dysfunctional. Its permeability increases, and above all, its capacity to evacuate waste produced by brain activity decreases.
The researchers showed that this failure is partly linked to an alteration of the LRP1 transporter. This is a protein responsible for exporting Aβ to the bloodstream. In patients and mouse models of Alzheimer's, LRP1 often remains mislocalized or degraded, preventing the clearance of Aβ and contributing to its toxic accumulation in the brain.
In this context, the role of the BBB is no longer passive, but active in the progression of the disease. It is this mechanism that the team chose to target. Not bypassing the barrier, but repairing it and restoring its ability to eliminate pathogenic proteins. This approach, which was marginal for a long time, is now proving to bring unprecedented results.
Active nanoparticles to reset brain transport
Instead of just being used to carry a drug, the nanoparticles used in this study act directly as a treatment. They are designed to target a specific protein, called LRP1, located on the cells that form the barrier between the brain and blood, the blood-brain barrier (BBB). This protein plays a key role in the elimination of toxic waste produced by the brain, such as amyloid-β (Aβ), implicated in Alzheimer's.
But for the system to work, the link between the nanoparticles and LRP1 must be well dosed. Neither too strong, to avoid blocking transport, nor too weak, to avoid being ineffective. The researchers therefore created nanoparticles carrying exactly 40 copies of a small element called angiopep-2, capable of attaching to LRP1. This precise dosage allows them to activate a natural cleansing pathway without destroying the components involved.
Injected into the blood of mice suffering from the equivalent of Alzheimer's, these nanoparticles cause a 50% reduction in toxic proteins in the brain in just two hours. At the same time, the quantity of these wastes increases sharply in the blood, which shows that they have been successfully evacuated.
Imaging studies and analyzes of the brain after treatment confirm that amyloid plaques have significantly decreased. The brain barrier also regains its normal functioning. These results show that nanomedicine can play an active role in repairing the brain's natural protective mechanisms, and no longer just by delivering a drug.
Prolonged cognitive recovery in treated mice
Beyond the measurable biological effects, the researchers wanted to evaluate the functional consequences of the treatment on the cognitive abilities of the animals. The treated mice, aged 12 months (equivalent to a 60-year-old human), were subjected to a series of behavioral tests over a period of six months.
In the Morris water maze test, which assesses spatial memory, animals receiving three injections of A40-POs found performance comparable to that of healthy mice. They locate the submerged platform more quickly and show better spatial orientation. They spend more time in the target area during memory tests.
These improvements persist. Six months after treatment, treated mice still had higher scores than untreated mice. Which confirms a stabilization of cognitive functions. Furthermore, their daily behavior improves. They build better quality nests, a reliable indicator of well-being and motor coordination. And they show an increased preference for sweet solutions, a sign of a positive emotional state.
Post-mortem brain analyzes show a lasting reduction in amyloid load, regulation of transport proteins (LRP1 up, Rab5 down), and restoration of vascular morphology. This consistency between biological and behavioral data confirms that the treatment is not limited to transient effects. It leads to overall and prolonged recovery.
Lorena Ruiz Pérez (IBEC), co-author, insists in a press release: “ It is not only a reduction in plaque, but a functional recovery of the brain which allows animals to return to normal life. “.
Towards a therapy targeting the vascular mechanics of the brain
Researchers have thus opened the way to a new therapeutic approach for Alzheimer's disease focused on repairing the vascular functions of the brain. This strategy radically moves away from current treatments, often limited to Aβ-neutralizing antibodies or symptomatic molecules.
The fundamental concept is based on the “reprogramming” of the transport mechanisms of the BBB. By reactivating the PACSIN2 pathway and preserving LRP1, nanoparticles restore efficient waste elimination dynamics. The issue is twofold. It is necessary to evacuate the Aβ already accumulated, but also to prevent the appearance of new plaques. And while maintaining a stable metabolic balance in the brain.
This approach therefore acts upstream and downstream of the pathological process. It could be adapted to other neurological diseases involving the BBB, such as Parkinson's or multiple sclerosis. Giuseppe Battaglia believes that “ the BBB is not an obstacle to overcome, but an organ to be treated “.
However, challenges remain before the transition to humans. The differences between mice and humans—in terms of BBB composition, LRP1 distribution, and immune systems—will require fine-tuning. Models in vitro human brain cells, based on stem cells, are already under development to refine the targeting of nanoparticles.
The researchers also plan to explore ligand variants, adapted to human genetic polymorphisms. And they must check for the absence of long-term toxicity. If these steps are taken, this therapy could represent a credible alternative to current approaches. With the ambition to transform Alzheimer's care.
Source: Chen, J., Xiang, P., Duro-Castano, A. et al. “Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood–brain barrier transport”. Sig Transduct Target Ther 10331 (2025).
With an unwavering passion for local news, Christopher leads our editorial team with integrity and dedication. With over 20 years’ experience, he is the backbone of Wouldsayso, ensuring that we stay true to our mission to inform.
