Ashe Lab

The Ashe Lab research journey began with the creation of the Tg2576 transgenic mouse, a disease model that simulates the “pre-clinical” phase of Alzheimer’s disease by developing subtle memory problems and amyloid-beta plaques. This mouse model of Alzheimer’s disease is used around the world today. This work continued with the creation of additional mouse models of neurodegenerative disease, including the rTg4510 transgenic mouse, which develops tauneurofibrillary tangles.

Currently, our research continues to utilize these mouse models as we focus on understanding the mechanisms by which key proteins contribute to disease development and cognitive decline. We primarily use transgenic animal models, molecular biology, and cognitive testing to probe the underlying cause and pathology of Alzheimer’s disease. Specifically, we are investigating the structural and cellular biology of various forms of amyloid-beta and tau proteins; we believe that understanding the relationship between the structure of these proteins and their biological effects is the key to identifying what forms are responsible for neurodegeneration and memory loss in Alzheimer’s disease.

As we characterize numerous mouse models of disease and cognitive impairment, our team utilizes cutting-edge laboratory technologies to study key pathways and proteins. A major aim of our current research is to understand the role of a protein known as Caspase-2 in aging and neurodegenerative disease. We demonstrated that Caspase-2 cuts tau protein to generate a smaller fragment, known as Δtau314. Lowering Caspase-2 and Δtau314 halts the mislocalization of tau and helps maintain healthy brain cell connections. Furthermore, we demonstrated the therapeutic potential of this mechanism by reducing Caspase-2, lowering Δtau314 levels, and reversing existing memory impairment in our mouse models.

As we study the fundamental biology, characteristic disease pathology, and associated cognitive decline, we strive to elucidate effective therapeutic targets for drug development. Our science is rapidly advancing through several exciting collaborations with the some of the best geneticists and medicinal chemists in the world.