Early in her career while she was doing cancer research at Harvard, Li-Huei Tsai began working on a protein called Cdk5. She discovered that the enzyme is regulated in neurons by cofactor proteins p35 and p39. Her lab further discovered that when p35 is cleaved to a more stable form, p25, during excitotoxic injury, Cdk5 activity can become excessive.

But what does excessive Cdk5 activity mean? In 2003, in Neuron, her lab introduced a p25-inducible transgenic mouse, which has become a valuable mouse model of Alzheimer’s disease (AD) because it shows the hallmark neuronal and synapse loss in addition to the expected neurofibrillary tangles, amyloid pathology, and cognitive deficits of the disorder.

In Cell in 2014, her group also unveiled a new cleavage-resistant p35 mutant “knock-in” mouse, conclusively showing that synaptic depression induced by amyloid beta is completely corrected in the absence of p25, as are hallmark pathologies and symptoms of AD in mouse models of familial forms of the disease.

In 2015 in Nature,  Li-Huei’s group went on to show that in tissues from a brain region called the hippocampus, which is crucial for memory, the transcriptomic and epigenomic profiles of the p25-inducible mouse and human AD patients are remarkably similar. This mouse model has subsequently been well validated by other research groups as an especially close facsimile of human AD pathology.