Tau Enters Mitochondria, Revealing Another Path for Alzheimer’s Drug Development

Alzheimer’s drug development has long centered on amyloid and tau accumulation. Now, a study led by Stanford University researchers has shifted attention to the cell’s energy-producing core. The team proposes that tau may not only form neurofibrillary tangles, but may also directly enter mitochondria and reverse part of the electron flow, driving neuronal damage from within.

The study focused on “mitochondrial reverse electron transport” (RET). Under normal conditions, mitochondria produce the energy cells need along the electron transport chain. The researchers found that more highly phosphorylated tau binds directly to NDUFS3, a subunit of mitochondrial complex I, causing electrons to flow in reverse. This process generates excessive reactive oxygen species and lowers the ratio of NAD⁺ to NADH, disrupting the cell’s redox balance.

The damage does not occur in only one direction. The oxidative stress and inflammatory signals produced after RET increases promote further tau phosphorylation, creating a self-reinforcing cycle. The research team therefore believes this pathway may fill a long-standing gap in understanding: how tau abnormalities are connected to the mitochondrial dysfunction commonly seen in Alzheimer’s disease and other tauopathies.

The study included fruit flies, mice with tauopathy, and neurons cultured from human induced pluripotent stem cells. Genetically interfering with RET or using drugs to inhibit the process reduced oxidative stress, mitochondrial abnormalities, synaptic defects, and neuroinflammation. Learning and memory performance also improved in animal models. Analysis of postmortem brain tissue from patients with Alzheimer’s disease and progressive supranuclear palsy indicated that the same mechanism may be relevant to human disease.

This strategy differs from directly clearing tau: it seeks to interrupt the downstream circuit through which tau causes harm while avoiding the complete removal of tau’s normal functions. The study also found that different phosphorylation sites had varying effects on the binding of tau to NDUFS3, suggesting that precise future interventions may need to distinguish the tau states that actually drive toxicity rather than treating all tau as harmful.

However, the study is currently a preprint that has not yet completed peer review, and all therapeutic findings come from cell and animal experiments. RET may be involved in normal stress regulation, while complex I is also a critical part of energy metabolism. Whether long-term inhibition harms normal mitochondrial function, which patients might be suitable, and whether safe and effective exposure levels can be achieved in the human brain must still be answered through toxicology studies and human trials.

Two study authors, Bingwei Lu and Su Guo, have co-founded Cerepeut to attempt to translate this mechanism into a drug. The company describes CP-235 as a once-daily oral, small-molecule RET inhibitor capable of entering the central nervous system, but information on its efficacy and development status currently comes mainly from company materials, and there is not yet independently reviewed human clinical evidence. The true significance of this new pathway will depend on whether it can bridge the enormous gap between protective effects across multiple models and disease-modifying effects in patients.