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Alzheimer's Disease Research
Completed Award

Dr. Bradley Hyman

Bradley T. Hyman, M.D., Ph.D.

Massachusetts General Hospital
Charlestown, MA, United States

Title: Modeling the Intersection of Tau and Ab in Alzheimer Disease
Non-Technical Title: A Laboratory Model of the First Brain Changes in Alzheimer's

Co-PI(s):
Teresa Gomez-Isla, M.D., Ph.D.
Massachusetts General Hospital

Duration: July 1, 2011 - June 30, 2014
Award Type: Standard
Award Amount: $300,000

Summary:

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.

Details:

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 entorhinnal 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 entorhinnal 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 entorhinnal 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.

Publications:

de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, Spires-Jones TL, Hyman BT. Propagation of tau pathology in a model of early Alzheimer's disease.  Neuron. 2012 Feb 23;73(4):685-97 PubMed Icon Google Scholar Icon

Pooler AM, Polydoro M, Wegmann SK, Pitstick R, Kay KR, Sanchez L, Carlson GA, Gomez-Isla T, Albers MW, Spires-Jones TL, Hyman BT. Tau - amyloid interactions in the rTgTauEC model of early Alzheimer's disease suggest amyloid induced disruption of axonal projections and exacerbated axonal pathology. J Comp Neurol. 2013 Jul 10. doi: 10.1002/cne.23411. [Epub ahead of print] PubMed Icon Google Scholar Icon

Progress Updates:

Dr. Hyman’s and Dr. Gomez-Isla’s team performed initial experiments that were aimed at understanding if the tau protein, which makes up neurofibrillary tangles, propagates across different parts of the brain. The team’s experiments to date, published nearly at the same time as results of analogous experiments from scientists at Columbia, suggest that tau can escape from one neuron and pass on to additional neurons in the system. They are now searching for the mechanisms of tau protein escape from one cell and uptake by another, and learning more about the consequences of this phenomenon.

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