Tabuchi Katsuhiko, Chen Guiquan, Südhof Thomas C, Shen Jie
Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, California 94304-5543, USA.
J Neurosci. 2009 Jun 3;29(22):7290-301. doi: 10.1523/JNEUROSCI.1320-09.2009.
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.
成年小鼠大脑中早老素功能丧失会导致记忆丧失和与年龄相关的神经退行性变。由于早老素具有γ-分泌酶依赖性和非依赖性活性，目前尚不清楚早老素依赖性记忆形成和神经元存活需要哪种活性。为了解决这个问题，我们构建了出生后前脑特异性尼卡斯特林条件性敲除（cKO）小鼠，其中γ-分泌酶的一个亚基尼卡斯特林在大脑皮层成熟兴奋性神经元中被选择性失活。尼卡斯特林cKO小鼠在学习和记忆方面表现出进行性损伤，并表现出年龄依赖性的皮层神经元丢失，伴有星形胶质细胞增生、小胶质细胞增生和微管相关蛋白Tau的过度磷酸化。尼卡斯特林cKO小鼠中观察到的神经退行性变可能通过凋亡发生，凋亡神经元数量增加证明了这一点。这些发现证明了尼卡斯特林在学习和记忆的执行以及大脑中神经元存活的维持中起着至关重要的作用，并表明早老素通过其作为γ-分泌酶亚基的作用在记忆和神经元存活中发挥功能。
