![The Tonks lab studied PTP1B inhibition in a mouse model of Alzheimer’s disease. When PTP1B was deleted, as shown in the bottom row, the brain’s immune cells (green) were better at engulfing harmful amyloid-β plaques (grey), as shown in the left column. [Cold Springs Harbor Laboratory]](https://sp-ao.shortpixel.ai/client/to_webp,q_glossy,ret_img,w_750,h_375/https://www.psypost.org/wp-content/uploads/2026/02/img-750x375.jpg)
A protein long implicated in diabetes and obesity may hold the key to treating Alzheimer’s disease by reinvigorating the brain’s immune system. New research suggests that blocking this protein, known as PTP1B, allows immune cells to clear toxic waste more effectively and restores cognitive function in mice. The findings were published in the Proceedings of the National Academy of Sciences.
Alzheimer’s disease is characterized by the accumulation of sticky protein clumps called amyloid-beta. These plaques disrupt communication between brain cells and are widely believed to drive memory loss and neurodegeneration. The brain relies on specialized immune cells called microglia to maintain a healthy environment. In a healthy brain, microglia locate and engulf toxic clumps like amyloid-beta through a process called phagocytosis.
However, in patients with Alzheimer’s, these immune cells often become lethargic. They fail to keep up with the accumulating waste, allowing plaques to spread. Scientists have struggled to find ways to safely reactivate these cells without causing damaging inflammation.
There is a growing body of evidence linking Alzheimer’s to metabolic disorders. Conditions like type 2 diabetes are well-established risk factors for dementia. This connection led researchers to investigate a specific enzyme called protein tyrosine phosphatase 1B, or PTP1B.
This enzyme acts as a brake on signaling pathways that control how cells use energy and respond to insulin. Nicholas K. Tonks, a professor at Cold Spring Harbor Laboratory who discovered PTP1B in 1988, led the investigation along with graduate student Yuxin Cen. They hypothesized that PTP1B might be preventing microglia from doing their job.
To test this theory, the team used a mouse model genetically engineered to develop Alzheimer’s-like symptoms. These mice, known as APP/PS1 mice, typically develop amyloid plaques and memory deficits as they age. The researchers created a group of these mice that lacked the gene responsible for producing PTP1B. When these mice reached an age where memory loss typically begins, the researchers assessed their cognitive abilities.
The mice lacking the enzyme performed better on memory tests than the standard Alzheimer’s mice. One test involved a water maze where mice had to remember the location of a hidden platform. The mice without PTP1B found the escape route faster, indicating superior spatial learning. Another test measured how much time mice spent exploring a new object versus a familiar one. The genetically modified mice showed a clear preference for the new object, a sign of intact recognition memory.
The team also tested a drug designed to inhibit PTP1B to see if pharmacological intervention could mimic the genetic deletion. They administered a compound called DPM1003 to older mice that had already developed plaques. After five weeks of treatment, these mice showed similar improvements in memory and learning. This suggested that blocking the enzyme could reverse existing deficits and was not just a preventative measure.
Next, the investigators examined the brains of the animals to understand the biological changes behind these behavioral improvements. They used staining techniques to visualize amyloid plaques. Both the mice lacking the PTP1B gene and those treated with the inhibitor had considerably fewer plaques in the hippocampus. This region of the brain is essential for forming new memories.
To understand how the plaques were being cleared, the researchers analyzed the gene activity in individual brain cells. They performed single-cell RNA sequencing to look at the genetic profiles of thousands of cells. They found that PTP1B is highly expressed in microglia. When the enzyme was absent, the microglia shifted into a unique state.
These cells began expressing genes associated with the consumption of cellular debris. This state is often referred to as “disease-associated microglia,” or DAM. While the name sounds negative, this profile indicates cells that are primed to respond to injury. The lack of PTP1B appeared to push the microglia toward this beneficial, cleaning-focused phenotype.
The researchers then isolated microglia in a dish and exposed them to amyloid-beta to observe their behavior directly. Cells lacking PTP1B were much more efficient at swallowing the toxic proteins. “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.”
The study revealed that this boost in activity was powered by a change in cellular metabolism. Phagocytosis is an energy-intensive process. The immune cells without PTP1B were able to ramp up their energy production to meet this demand. They increased both their glucose consumption and their oxygen use.
This metabolic surge was driven by the PI3K-AKT-mTOR signaling pathway. This is a well-known cellular circuit that regulates growth and energy survival. In the absence of PTP1B, this pathway remained active, providing the fuel necessary for the microglia to function.
Finally, the team identified the specific molecular switch that PTP1B controls to regulate this process. They found that the enzyme directly interacts with a protein called spleen tyrosine kinase, or SYK. SYK is a central regulator that tells microglia to activate and start eating. PTP1B normally removes phosphate groups from SYK, which keeps the kinase in an inactive state.
When PTP1B is removed or inhibited, SYK becomes overactive. This triggers a cascade of signals that instructs the cell to produce more energy and engulf amyloid. The researchers confirmed this by adding a drug that blocks SYK to the cells. When SYK was blocked, the benefits of removing PTP1B disappeared, and the microglia stopped clearing the plaque. This proved that PTP1B works by suppressing SYK.
The researchers utilized a “substrate-trapping” technique to confirm this direct interaction. They created a mutant version of PTP1B that can grab onto its target protein but cannot let go. This allowed them to isolate the PTP1B enzyme and see exactly what it was holding. They found it was bound tightly to SYK, confirming the direct relationship between the two proteins.
While these results are promising, the study was conducted in mice. Animal models mimic certain aspects of Alzheimer’s pathology but do not perfectly replicate the human disease. Future research will need to determine if similar metabolic and immune pathways are active in human patients. Additionally, PTP1B regulates many systems in the body, so widespread inhibition must be tested for safety.
The researchers are now interested in developing inhibitors that can specifically target the brain to minimize potential side effects. The Tonks lab is working to refine these compounds for potential clinical use. Tonks envisions a strategy where these inhibitors are used alongside existing treatments. “The goal is to slow Alzheimer’s progression and improve quality of life of the patients,” says Tonks. “Using PTP1B inhibitors that target multiple aspects of the pathology, including Aβ clearance, might provide an additional impact,” says Ribeiro Alves.
The study, “PTP1B inhibition promotes microglial phagocytosis in Alzheimer’s disease models by enhancing SYK signaling,” was authored by Yuxin Cen, Steven R. Alves, Dongyan Song, Jonathan Preall, Linda Van Aelst, and Nicholas K. Tonks.
