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2006 Grant - Kelleher
A Knock-In Mouse Model of Presenilin-Linked Frontotemporal Dementia
Raymond J. Kelleher III, M.D., Ph.D.
Massachusetts General Hospital
2006 Investigator-Initiated Research Grant
Some people with Alzheimer's disease acquire the disorder by inheriting one of three mutated genes. Two of the genes are called PS1 and PS2, which provide "blueprints" for the production of the proteins presenilin 1 and presenilin 2, respectively. These proteins are known to help produce the beta-amyloid protein fragment, a key suspect in Alzheimer pathology.
Scientists often study Alzheimer's disease processes using mice genetically engineered to develop an Alzheimer-like disorder. One of the problems with many of these mouse models of the disease is that they rarely exhibit significant brain cell loss or other brain damage even though they develop deposits of beta-amyloid and memory impairments.
In a recent study Raymond J. Kelleher III, M.D., Ph.D., and colleagues found that the inactivation of both PS1 and PS2 in the brains of adult mice causes severe cell loss and damage even though beta-amyloid production is markedly lower. These results suggest that presenilins play a critical role in the mechanisms that control learning, memory and brain cell survival.
With this grant, Dr. Kelleher's team will be investigating the role of presenilin mutations in frontotemporal dementia, a disease similar to Alzheimer's but not characterized by beta-amyloid deposits. The investigators will genetically engineer mice to carry a mutated PS1 gene associated with frontotemporal dementia. They will then analyze whether these mice develop brain damage similar to that found in their earlier study of Alzheimer-like mice with inactivated PS1 and PS2.
This work will involve analyzing such factors as cell-to-cell communication in the brain, the formation of memory and the survival of brain cells. The study's results may shed new light on pathological events in frontotemporal dementia, Alzheimer's disease and related brain disorders.