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- Title
Conditional Forebrain Inactivation of Nicastrin Causes Progressive Memory Impairment and Age-Related Neurodegeneration.
- Authors
Tabuchi, Katsuhiko; Guiquan Chen; Südhof, Thomas C.; Jie Shen
- Abstract
Loss of presenilin function in adult mouse brains causes memory loss and age-related neurodegeneration. Since presenilin possesses γ-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 γ-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 γ-secretase subunit.
- Subjects
CEREBRAL cortex; PRESENILINS; NEURODEGENERATION; PROSENCEPHALON; DEGENERATION (Pathology); PATHOLOGY
- Publication
Journal of Neuroscience, 2009, Vol 29, Issue 22, p7290
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1320-09.2009