Conditional forebrain inactivation of nicastrin causes progressive memory impairment and age-related neurodegeneration.
Conditional forebrain inactivation of nicastrin causes progressive memory impairment and age-related neurodegeneration.
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DOI：
10.1523/jneurosci.1320-09.2009
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发表时间：
2009-06-03
期刊：
影响因子：
--
通讯作者：
Shen J
中科院分区：
文献类型：
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作者：
Tabuchi K;Chen G;Südhof TC;Shen J
成年小鼠大脑中早老素功能的丧失会导致记忆丧失和与年龄相关的神经变性。由于早老素具有γ-分泌酶依赖性和非依赖性活性，因此尚不清楚哪种活性是早老素依赖性记忆形成和神经元存活所必需的。为了解决这个问题，我们制造了出生后的前脑特异性nicastrin条件敲除（cKO）小鼠，在这些小鼠中，nicastrin （γ-分泌酶的一个亚基）在大脑皮层的成熟兴奋性神经元中选择性失活。Nicastrin 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皮质神经元丧失，伴有星形细胞增生、小胶质细胞增生和微管相关蛋白Tau的过度磷酸化。nicastrin cKO小鼠观察到的神经变性可能通过凋亡发生，凋亡神经元数量增加。这些发现表明nicastrin在大脑学习和记忆的执行以及神经元存活的维持中起着重要作用，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起作用。
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 knockout (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.