Alzheimer’s can be resemble a great fortress with a large number of defenses that makes it very difficult for us. One of its most formidable defenses is blood brain barriera biological wall that protects the brain from harmful substances, but, ironically, also prevents the entry of most drugs. In Alzheimer’s patients, this barrier not only blocks help, but also becomes an accomplice to the disease. But we have already found a way to access and attack this pathology.
The investigation. A team of scientists has been able to develop a radically new strategy to treat Alzheimer’s. Instead of trying to force entry into the brain, they have created smart nanocapsules that “reprogram” the barrier itself to do its job again: actively cleaning up toxic waste.
Something that they have already tested in mice, and they have given spectacular results: a reduction of almost 45% of the amyloid load in just two hours and a cognitive recovery that was maintained for six months.
The problem. In order to understand this advance, we must know exactly how ‘access’ to our brain works. The blood-brain barrier (BBB) functions as an incredibly strict customs checkpoint. Like any border, it must have an entry and exit gate and in this case it is the LRP1 receiver.
In the case of a healthy brain, LRP1 will be responsible for capturing beta-amyloid proteins and transporting them out of the brain for elimination. But in the case of a brain that is already old, and more markedly in Alzheimer’s, the amount of these LRP1 receptors is reduced, causing beta-amyloid to end up accumulating in our neurons, causing this disease to begin to show signs of presence.
The discovery. In this case, the research team discovered that the fate of the LRP1 receptor depends on how it interacts with the molecules that bind to it. This is where the concept of “greedy,” or total bonding strength, comes into play.
Very strong union. If a molecule clings too tightly to LRP1 (as beta-amyloid aggregates do in Alzheimer’s), the receptor activates an emergency pathway that sends it directly to be destroyed in the cellular “dumping ground” that is the lysosomes. This makes the problem even worse, as it eliminates the few exit doors left in the brain to take out the ‘garbage’.
Moderate union. Or average greed. If the binding is “just right,” the receptor activates a non-destructive express transport pathway (the PACSIN2 pathway). This pathway creates a kind of tubular tunnel that transports cargo through the barrier quickly and safely, preserving the LRP1 receptor so it can continue working. In fact, this pathway even promotes the expression of more LRP1 receptors, which is what interests us most in this situation.
The result. Based on this principle, the researchers designed nanocapsules called “polymersomes” (A₄₀-POs). They are tiny spheres decorated with a very specific number of “keys” (angiopep-2 ligands) on their surface. The number of these keys was calculated to achieve that perfect “medium greed”, with the aim of achieving the result similar to that of a moderate union.
Results. When they administered these nanocapsules to model mice with advanced Alzheimer’s, the effects were surprising. A massive brain cleanse was achieved in just two hours, causing beta-amyloid protein levels in the mice’s brains to be reduced by 45%.
In order to confirm that the protein was not just moving from place to place, its blood levels were measured. The result was an 8-fold increase, which shows that the blood-brain barrier was expelling the ‘waste’.
The tests. In order to see the result in practice, behavioral tests such as the Morris water maze were carried out. Here treated Alzheimer’s mice showed significant improvement in spatial learning and memory. In this case, their performance became comparable to healthy mice without the disease.
Most strikingly, these cognitive benefits persisted for up to six months after a single course of treatment, suggesting a long-term restorative effect.
More than a drug. This work represents a paradigm shift. Most therapeutic strategies for Alzheimer’s treat the blood-brain barrier as an obstacle to overcome. This new approach treats it as a dysfunctional biological system that can be repaired by adding more exit doors for the organism to maintain this homeostasis.
By using these nanocapsules with the “perfect keychain”, not only is the existing beta-amyloid removed, but the brain’s natural cleaning mechanism is reactivated. The treatment was able to restore levels of LRP1 and the beneficial transport pathway (PACSIN2) while reducing the destructive pathway. In essence, nanocapsules are not the drug itself, but a tool to reprogram the biology of the brain so that it heals itself.
Although the results have been obtained in mouse models and the path to human trials is long and complex, this research opens a completely new and hopeful therapeutic avenue. The idea of ”repairing the barrier instead of just breaking it down” could be the key not only to Alzheimer’s, but also to other neurodegenerative diseases where transport and brain clearance play a key role.
Images | Bhautik Patel
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