Cerepeut's Lead Compound Shows How a Little-Known Mitochondrial Mechanism Fuels Neurodegeneration, and How to Stop It

SAN CARLOS, Calif.--(BUSINESS WIRE)--Cerepeut, Inc., a biotechnology company developing mitochondrial therapeutics for neurodegenerative disease, today announced publication of a landmark study in Neuron revealing why the brain turns on itself in Alzheimer's disease and related disorders, and unveiling a drug candidate designed to stop it.

Breaking the loop, rather than only clearing tau after the fact, is a powerful way to change the course of disease.

Share

Tau is a well-known driver of Alzheimer's, notorious for clumping into toxic tangles inside dying neurons. What scientists didn't know was that tau also moonlights as a switch inside mitochondria, the cell's power plants, and that when this switch gets stuck, it accelerates brain aging and disease.

The study, led by Cerepeut cofounders Bingwei Lu, Ph.D. (Stanford) and Su Guo, Ph.D. (UCSF), shows for the first time that tau directly engages the mitochondrial machinery controlling reverse electron transport (RET). In a healthy brain, RET is tightly regulated. In a diseased or aging brain, phosphorylated tau (pTau) overactivates RET, which drives more tau phosphorylation, forming a self-perpetuating cycle.

"Once that loop takes hold, it becomes a self-sustaining engine of neurodegeneration," said Lu. "Breaking the loop, rather than only clearing tau after the fact, is a powerful way to change the course of disease."

The team found this same overactive RET signal in animal models of tauopathy and in human Alzheimer's brain tissue, confirming the mechanism as a real feature of human disease.

CP-235 Breaks the Loop

Using Cerepeut's lead compound CP-235, researchers showed that inhibiting RET breaks the cycle at its source, lowering pTau without affecting total tau. Reproduced across fruit flies, rTg4510 mice, and human stem cell-derived neurons, CP-235 (CPT in the study) rescued cognitive deficits, reduced brain atrophy, protected neurons from degeneration, and calmed neuroinflammation.

"We now have a therapeutic candidate, and a validated biological target in RET that gets at the root cause of pTau-driven brain disease rather than only mopping up after the damage is done," said Hua Tu, Ph.D., President and CEO of Cerepeut. "CP-235 was well tolerated across every model we tested, so we believe RET is not just a promising target, it's a druggable one."

Because the pTau-RET loop cuts across multiple tauopathies, the implications extend beyond Alzheimer's to progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), corticobasal degeneration (CBD), and the broader biology of brain aging. Cerepeut is advancing its lead program toward clinical development for these diseases.

The study reflects a collaboration among Cerepeut and research teams at Stanford University School of Medicine's Department of Pathology and multiple UCSF departments and centers, including the Memory and Aging Center, Neurology, Pathology, Bioengineering and Therapeutic Sciences, and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research.

Study Highlights

• Discovers a previously unknown job for tau: regulating mitochondrial RET through direct engagement with Complex I.
• Identifies a self-perpetuating cycle in diseased brain cells: pTau overactivates RET, and RET drives even more pTau.
• Shows that CP-235 (CPT) inhibits RET, breaks the cycle, and lowers pTau.
• Demonstrates that CP-235 rescues cognitive deficits, reduces brain atrophy, halts neurodegeneration, and reduces neuroinflammation across flies, mice, and human iPSC-derived neurons.
• Confirms RET activation in both animal models and human patient brain tissue.
• Positions RET as a promising, well-tolerated therapeutic target for tauopathies and Alzheimer's disease.

About Cerepeut

Cerepeut is a biotechnology company restoring mitochondrial resilience in neurodegenerative disease and age-related decline. Its first-in-class small molecule, CP-235, targets pathological mitochondrial RET to break the pTau-RET feedback loop, reduce oxidative stress, and preserve neuronal function. Cerepeut's lead program is advancing toward clinical development for tau-related neurodegenerative diseases.

For more information, visit cerepeut.com. View the study: https://www.cell.com/neuron/abstract/S0896-6273(26)00541-6