2005 Investigator-Initiated Research Grant

Transgenic animals are engineered to carry DNA from a genetically different species, such as a human. Scientists often use transgenic animals to mimic and study human diseases. Richard E. Brown, Ph.D., and colleagues will use double transgenic mice to model disease processes caused by mutations in two Alzheimer-linked genes: PS1, the genetic instructions for making the presenilin-1 protein, and APP, the instructions for amyloid precursor protein.

One function of presenilin-1 is to work with other proteins to chop up amyloid precursor protein into smaller pieces. This action gives rise to beta-amyloid, which is the major component found in the amyloid plaques that accumulate in the brains of people with Alzheimer’s disease. Specific mutations in both these genes are known to cause rare but particularly aggressive forms of the disease, characterized by relatively Early-Onset and rapid progression.

Brown and colleagues will integrate PS1 and APP genes carrying those mutations into mouse chromosomes. These double transgenic mice, like others, develop amyloid plaques, but unlike others, they experience a massive loss of brain cells that more closely models the effect of Alzheimer’s disease in humans.

The researchers will use a battery of tests to determine if the mice also suffer from the same cognitive and behavioral problems found in people with Alzheimer’s disease. The animals will be subjected to a variety of tests including cognitive tests for learning, memory and decision making; noncognitive tests for emotional, sensory and motor disturbances; and test of other complex cognitive skills. The aim is to determine whether these mice accurately model the cognitive and behavioral symptoms found in humans. Findings from this work may be beneficial to a number of studies dependent of valid animal models.