In Alzheimer’s disease, harmful amyloid beta buildup is thought to drive the illness. Studies show that brain immune cells struggle to clear this buildup.
A new study from Cold Spring Harbor Laboratory Professor Nicholas Tonks, graduate student Yuxin Cen, and postdoctoral fellow Steven Ribeiro Alves found that blocking a protein called PTP1B helped mice with Alzheimer’s, improving memory and reducing amyloid beta levels.
The study shows that PTP1B interacts with a protein called spleen tyrosine kinase (SYK), which helps brain immune cells (microglia) clear waste like amyloid beta. Removing PTP1B improved SYK’s function, boosting microglia’s ability to clear debris and improving their energy use.
Cen said, “Over the course of the disease, these cells become exhausted and less effective,” says Cen. “Our results suggest that PTP1B inhibition can improve microglial function, clearing up Aβ plaques.”
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Microglia, the brain’s immune cells, make a lot of PTP1B. When this protein is removed, the cells switch on more strongly, becoming better at clearing waste and using energy. This boost is linked to the AKT-mTOR pathway, which helps meet the energy needs of active cells.
The team also demonstrated that blocking SYK allowed PTP1B to work through this pathway to regulate microglial activity. This makes PTP1B an important player in microglial function and a possible target for Alzheimer’s treatment.
Obesity and type 2 diabetes are known risk factors for Alzheimer’s disease and may help explain why it’s becoming more common. Since PTP1B is already a proven target in these conditions, it provides scientists with another reason to study it in Alzheimer’s. Current Alzheimer’s treatments mainly aim to clear amyloid beta, but they provide only limited benefits for many patients.
“Using PTP1B inhibitors that target multiple aspects of the pathology, including Aβ clearance, might provide an additional impact,” says Ribeiro Alves.
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The Tonks lab is working with DepYmed, Inc., to develop drugs that block PTP1B for various uses. For Alzheimer’s, Tonks suggests combining current approved treatments with PTP1B blockers.
He says the aim is to slow the disease and improve patients’ lives. This research shows PTP1B could be an important new target for Alzheimer’s therapy.
Journal Reference:
- Yuxin Cen, Steven R. Alves, Dongyan Song and Nicholas K. Tonks. PTP1B inhibition promotes microglial phagocytosis in Alzheimer’s disease models by enhancing SYK signaling. PNAS. DOI: 10.1073/pnas.2521944123
