Age is the most significant risk factor for Alzheimer’s disease (AD) and impacts every system of our bodies. Several years ago, Dr. Villeda conducted an elegant experiment demonstrating the profound impact age has on our brain health.
He used a procedure called heterochronic parabiosis, in which two animals are surgically joined so that they share the same circulatory system. In this case, he joined old mice to young mice, allowing them to continuously exchange blood.
The results were striking. The old mice showed dramatic improvements in cognitive function. Dr. Villeda found the same improvement when he tested mice that produce Alzheimer’s pathology: connecting them to young mice boosted their brain function.
The old mice’s blood was clearly missing something that young blood contained. Simply providing that missing factor through the shared circulation was enough to reverse cognitive decline, even in the presence of Alzheimer’s pathology.
Dr. Villeda’s goal is to identify exactly what’s missing from aging blood—and whether restoring it could help treat or prevent AD.
In subsequent experiments, the Villeda lab found that transferring only platelets from a young mouse into an old mouse was sufficient to induce the same benefits they observed when the mice shared a circulatory system. Platelets are small circulating blood cells primarily responsible for forming clots when a blood vessel is damaged. Beyond this, platelets play a role in inflammatory signaling. His lab also identified a specific platelet protein called platelet factor 4 (PF4), whose expression declines substantially with age. Administering PF4 to aged mice once again improved cognition. For this proposal, he plans to build on the strong data he has already gathered and test whether young platelets and PF4 can reduce AD pathology.
The proposal contains two experimental aims. In the first, Dr. Villeda’s lab will collect platelets from young mice and administer them to aged mice with aggressive amyloid pathology. They will then assess the changes in cognitive function, neuroinflammation, synaptic plasticity, and amyloid pathology. The second aim will determine whether PF4 is responsible for the changes seen in Aim 1. For this aim, the Villeda lab will only administer PF4 and then measure the same outcomes as in the first aim. In addition, they will investigate how microglia respond to PF4 infusions. Other studies have shown that PF4 can reduce microglial inflammation, and Dr. Villeda wants to determine if the same occurs in the context of amyloid pathology.
This study continues a crucial line of work aimed at identifying the underlying factors in blood that are lost with age. The potential for a blood-based Alzheimer’s treatment is particularly exciting. It would avoid one of the biggest challenges in drug development: getting medications across the blood-brain barrier and into the brain. Such a treatment would have a profound benefit for AD patients on a scale that current treatments are not capable of.
