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The Journal of Neuroscience, June 3, 2009, 29(22):7290-7301; doi:10.1523/JNEUROSCI.1320-09.2009

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Neurobiology of Disease
Conditional Forebrain Inactivation of Nicastrin Causes Progressive Memory Impairment and Age-Related Neurodegeneration

Katsuhiko Tabuchi,1,2 * Guiquan Chen,3 * Thomas C. Südhof,1,2 and Jie Shen3

1Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, California 94304-5543, 2Department of Neuroscience and Molecular Genetics, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and 3Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Dr. Jie Shen, Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115. Email: jshen{at}rics.bwh.harvard.edu

Loss of presenilin function in adult mouse brains causes memory loss and age-related neurodegeneration. Since presenilin possesses {gamma}-secretase-dependent and -independent activities, it remains unknown which activity is required for presenilin-dependent memory formation and neuronal survival. To address this question, we generated postnatal forebrain-specific nicastrin conditional knock-out (cKO) mice, in which nicastrin, a subunit of {gamma}-secretase, is inactivated selectively in mature excitatory neurons of the cerebral cortex. nicastrin cKO mice display progressive impairment in learning and memory and exhibit age-dependent cortical neuronal loss, accompanied by astrocytosis, microgliosis, and hyperphosphorylation of the microtubule-associated protein Tau. The neurodegeneration observed in nicastrin cKO mice likely occurs via apoptosis, as evidenced by increased numbers of apoptotic neurons. These findings demonstrate an essential role of nicastrin in the execution of learning and memory and the maintenance of neuronal survival in the brain and suggest that presenilin functions in memory and neuronal survival via its role as a {gamma}-secretase subunit.

Received March 18, 2009; revised May 5, 2009; accepted May 7, 2009.

Correspondence should be addressed to Dr. Jie Shen, Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115. Email: jshen{at}rics.bwh.harvard.edu






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