Disruption of neurogenesis by amyloid β-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease
Disruption of neurogenesis by amyloid β-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease
复制标题
DOI：
10.1046/j.1471-4159.2002.01267.x
复制
发表时间：
2002-12-01
影响因子：
4.7
通讯作者：
Mattson, MP
中科院分区：
文献类型：
--
作者：
Haughey, NJ;Nath, A;Mattson, MP
神经发生发生在成年哺乳动物的大脑中，并可能在学习和记忆过程中发挥作用，并从损伤中恢复，这表明神经祖细胞（NPC）的异常可能有助于人类学习和记忆障碍的发病机制。本研究的目的是确定是否NPC的增殖，生存和神经元分化受损的阿尔茨海默病（AD）的转基因小鼠模型，并确定致病形式的淀粉样β肽（Abeta）对培养的NPC的生存和神经元分化的影响。在转基因小鼠中，海马齿状回中NPC的增殖和存活减少，转基因小鼠的淀粉样前体蛋白突变形式导致早发性家族性AD。Abeta通过细胞钙稳态失调以及钙蛋白酶和半胱氨酸蛋白酶的激活来损害培养的人和啮齿动物NPC的增殖和神经元分化，并促进神经元限制性NPC的凋亡。Abeta对NPC的不良影响可能与AD的神经元耗竭和认知功能障碍有关。
Neurogenesis occurs in the adult mammalian brain and may play roles in learning and memory processes and recovery from injury, suggesting that abnormalities in neural progenitor cells (NPC) might contribute to the pathogenesis of disorders of learning and memory in humans. The objectives of this study were to determine whether NPC proliferation, survival and neuronal differentiation are impaired in a transgenic mouse model of Alzheimer's disease (AD), and to determine the effects of the pathogenic form of amyloid beta-peptide (Abeta) on the survival and neuronal differentiation of cultured NPC. The proliferation and survival of NPC in the dentate gyrus of the hippocampus was reduced in mice transgenic for a mutated form of amyloid precursor protein that causes early onset familial AD. Abeta impaired the proliferation and neuronal differentiation of cultured human and rodent NPC, and promoted apoptosis of neuron-restricted NPC by a mechanism involving dysregulation of cellular calcium homeostasis and the activation of calpains and caspases. Adverse effects of Abeta on NPC may contribute to the depletion of neurons and cognitive impairment in AD.