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2011 Grants - Kelleher
Developing Knock-In Mouse Models of Loss of Presenilin Function in Familial Alzheimer's Disease (FAD)
Raymond J. Kelleher, M.D., Ph.D.
Massachusetts General Hospital
2011 Investigator-Initiated Research Grant
Presenilins are proteins of great interest to scientists studying Alzheimer's disease because mutations in the genes for presenilin are known to cause specific inherited forms of the disease (familial Alzheimer's disease, or FAD). How such mutations lead to disease is not well understood, but better knowledge of these mechanisms may increase our understanding of all forms of Alzheimer's disease.
Raymond J. Kelleher, M.D., Ph.D. and colleagues have been studying mutations in one of the presenilin genes (PS1). By studying human families that carry PS1 mutations (and therefore exhibit early onset Alzheimer's disease), they identified one specific mutation known as L435F. Using molecular genetic techniques, the researchers created a strain of mice with the exact same genetic mutation. They observed that the L435F mutation of PS1 causes the protein to be completely inactive, leading to the development of Alzheimer-like pathology.
To test whether inactivation of PS1 is common in other PS1 mutations, the researchers have identified another PS1 mutation in human families with early onset Alzheimer's disease. The researchers plan to create another strain of mice carrying this mutation, known as the C410Y mutation. They will then analyze how this mutation compares and contrasts with the L435F mutation in terms of PS1 function and the development of Alzheimer's-like brain pathology and dysfunction. These studies will provide valuable insights into the molecular mechanisms of Alzheimer's dementia, and new animal models with which to study potential treatments.