Modeling the Intersection of Tau and Ab in Alzheimer Disease

Alzheimer disease starts with neurofibrillary lesions in a special brain area, the entorhinal cortex, which is responsible for memory related brain functions. We propose to make a model of this stage of the disease by genetically engineering a mouse to develop these same lesions in only this brain area; doing so will allow us to study the earliest phase of the disease, and to learn about whether early lesions lead to disease progression.

The entorhinal cortex is the part of the brain that is responsible for communications to and from the hippocampus (which, in turn, is the part of the brain that’s important for creating and maintaining memories). In Alzheimer’s disease, brain lesions tend to start in the entorhinal cortex and “spread” to other parts, with devastating effects. One of the lesions formed in Alzheimer’s are called “tangles” that contain tau protein. Drs. Bradley Hyman, Teresa Gomez‐Isla, and colleagues will study how Alzheimer’s affects the entorhinal complex and how the lesions spread from this initial place of damage to other parts of the brain. They will create and study a new mouse model of Alzheimer’s where tau protein is directed to be expressed only in the entorhinal cortex. Amyloid, the other key molecule in Alzheimer’s affects the connections between neurons that originate in the entorhinal cortex. Other mouse models don’t address the spread of lesions, but this model is designed to isolate this key part of progression to later stages of Alzheimer’s. In the future, this model could then be used for testing treatments to halt the spread of the lesions, and the interaction of lesions, before they cause cell damage and death in other parts of the brain.