Conditional forebrain inactivation of nicastrin causes progressive memory impairment and age-related neurodegeneration.
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.
Tabuchi
Katsuhiko
K
Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, California 94304-5543, USA.
Chen
Guiquan
G
Südhof
Thomas C
TC
Shen
Jie
J
D000367:Age Factors; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D002478:Cells, Cultured; D003213:Conditioning, Psychological / Q000502:physiology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005106:Exploratory Behavior; D005239:Fear; D005911:Gliosis / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000503:physiopathology*; D053764:Presenilin-1 / Q000235:genetics; D016548:Prosencephalon / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; D053764:Presenilin-1; C485184:enhanced green fluorescent protein; C413604:nicastrin protein; D049452:Green Fluorescent Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D053829:Amyloid Precursor Protein Secretases