Disruption of transport mechanisms across the blood–brain barrier is considered one of the key factors contributing to β-amyloid accumulation in the brain. A new experimental study shows that modifying the avidity of ligands for the LRP1 receptor can influence its intracellular trafficking and restore transcytosis across the endothelium, opening up new therapeutic possibilities for Alzheimer’s disease.
Alzheimer’s disease (AD) is associated, among other factors, with impaired blood–brain barrier (BBB) function. BBB dysfunction is considered a crucial factor in the accumulation of Aβ plaques in the brain. In animal models as well as in patients with AD, the number of LRP1 (low-density lipoprotein receptor–related protein 1) molecules on the endothelial cell membrane is reduced. This decrease appears to be closely linked to barrier dysfunction and the gradual decline in cognitive function.
In the healthy brain, LRP1 is predominantly expressed in BBB endothelial cells, where it enables binding and transport of β-amyloid (Aβ) from the brain into the systemic circulation. Regulation of this system is, however, rather fragile: if LRP1 binds too many Aβ molecules too strongly via its ligands, the transport system becomes overloaded and LRP1 is degraded, further reducing its availability. Conversely, if binding is too weak, signaling is insufficient to initiate Aβ transport across the BBB. In both cases, Aβ accumulates.
The aim of the new study led by researchers from University College London was to determine whether this transport dysfunction could be reversed by optimizing ligand binding to the LRP1 receptor. To test this mechanism, supramolecular nanoparticles mimicking LRP1 ligands were developed.
The study was conducted in transgenic mice carrying human genes for amyloid precursor protein and presenilin-1, characterized by progressive Aβ deposition. The animals received a single intravenous dose of the experimental treatment. Two hours after administration, brain Aβ levels decreased by approximately 45%, while plasma Aβ levels increased eightfold. Cognitive testing in treated mice showed significant improvements in spatial memory and learning ability. These benefits persisted for up to six months.
The study’s lead author, Professor Giuseppe Battaglia, believes that the long-term effect of the treatment is due to restoration of cerebral vascular network function. Commenting on the team’s findings, he said: “When toxic substances such as Aβ accumulate, the disease progresses. However, once the vascular system starts functioning again, it begins clearing Aβ and other harmful molecules, allowing the entire system to regain balance.”
A single administration of supramolecular nanoparticles mimicking LRP1 ligands led, in a mouse model of AD, to rapid clearance of Aβ from the brain, restoration of blood–brain barrier transport mechanisms, and long-term improvement in cognitive function. This study is the first to show that appropriately tuned ligand avidity for LRP1 can alter the receptor’s intracellular trafficking and restore its transport function.
Although these are preclinical data, the work introduces a novel therapeutic concept: targeted repair of the barrier’s transport system rather than simply increasing drug penetration across the BBB. It represents a vascular therapy concept for AD based on reprogramming endothelial cells. Moreover, it opens the possibility of applying similar strategies to other diseases in which BBB transport balance is disrupted.
Editorial Team, Medscope.pro
Sources: 1. Chen J., Xiang P., Duro-Castano A. et al. Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood–brain barrier transport. Signal Transduct Target Ther 2025; 10 (1): 331, doi: 10.1038/s41392-025-02426-1. 2. Nanoparticles reverse Alzheimer’s pathology in mice. University College London 2025 Oct 9. Available at: www.ucl.ac.uk/news/2025/oct/nanoparticles-reverse-alzheimers-pathology-mice
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