Schematic illustration of the mechanism underlying togoPhosTAC-mediated targeted protein dephosphorylation.

Targeting a Harmful Change in Tau

Alzheimer’s disease is closely associated with the abnormal buildup of amyloid plaques in the brain. Tau, a protein that normally helps maintain the structural stability of nerve cells, also plays a role. When excessive phosphate groups attach to tau—a condition known as hyperphosphorylation—the protein can contribute to disease and amplify amyloid-related toxicity.

Despite growing understanding of this process, effective treatment strategies that precisely target and remove abnormal phosphate signals remain lacking.

“This technology works like a precise molecular GPS,” Hong-Ru Chen said. She likened excessive protein phosphorylation to a switch that activates harmful signaling inside nerve cells. Turning off that signal, she explained, could help reduce damage.

Part of the problem arises when phosphatases, the enzymes responsible for removing phosphate groups, become less active in the brain. As a result, abnormal phosphorylation can accumulate. The new technology directs these enzymes to tau, allowing them to remove phosphate groups at multiple disease-associated sites.

Delivering Treatment Through the Nose

The team tested a noninvasive approach by administering the treatment intranasally to mice with tau-related disease pathology. The treatment reached the brain and significantly reduced abnormal tau phosphorylation at several sites.

Fluorescence images show a marked reduction in phosphorylated tau (green, AT8 staining) in the brains of PS19 mice treated with togoPhosTAC (right), compared with untreated mice (left). Cell nuclei appear in blue. Scale bar: 20 μm.

In maze and recognition tests, treated mice showed improvements in spatial and short-term memory, along with reduced anxiety-like behavior.


Exploration heat maps show greater interest in a novel object (N) among togoPhosTAC-treated PS19 mice (right) than untreated mice (left), consistent with improved recognition memory. F marks the familiar object; warmer colors indicate more time spent in an area.

The researchers reported no detectable signs of neuronal damage or toxicity in the brain under the conditions tested. These findings remain preclinical. Further research is needed to determine whether the approach can be developed into a safe and effective treatment for people.

Potential Beyond Alzheimer’s Research

The platform’s applications may extend beyond tau. The team also demonstrated targeted removal of phosphate groups from epidermal growth factor receptor (EGFR), a protein implicated in cancer, and alpha-synuclein, which is associated with Parkinson’s disease.

By combining molecular targeting with nanotechnology, the researchers aim to develop a versatile approach to address abnormal protein phosphorylation across multiple diseases.

The team plans to further improve delivery to the brain as it works toward eventual clinical applications, with the long-term goal of expanding treatment options for neurodegenerative diseases.


Assistant Professor Hong-Ru Chen (right) and student Hsiang-Ying Lin (left) of NYCU’s Department of Life Sciences and Institute of Genome Sciences.