Oligomerization of Alzheimer's β-amyloid within processes and synapses of cultured neurons and brain
Oligomerization of Alzheimer's β-amyloid within processes and synapses of cultured neurons and brain
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DOI：
10.1523/jneurosci.5167-03.2004
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发表时间：
2004-04-07
影响因子：
5.3
通讯作者：
Gouras, GK
中科院分区：
文献类型：
--
作者：
Takahashi, RH;Almeida, CG;Gouras, GK
多种证据表明β -淀粉样蛋白（Abeta）参与阿尔茨海默病（AD）的发病机制，但Abeta参与的机制尚不清楚。向细胞外空间添加β可能具有神经毒性。神经元内Abeta42的积累也与神经变性有关。我们之前报道过，在Tg2576淀粉样前体蛋白突变转基因小鼠中，通过免疫电镜观察，脑Abeta42定位于多泡体外膜，并随着衰老而积累，特别是在神经元突起和突触室中。我们现在证明，Tg2576小鼠的原代神经元随着培养时间的推移再现了Abeta42在体内的定位和积累。此外，研究人员还发现，随着培养时间的推移，在Tg2576神经元以及Tg2576和人类AD大脑中，Abeta42在内体囊泡和神经元过程的微管中聚集成寡聚物。这些Abeta42寡聚物的积累与Tg2576小鼠和人类AD大脑过程和突触区室的病理改变有关。
Multiple lines of evidence implicate beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD), but the mechanisms whereby Abeta is involved remain unclear. Addition of Abeta to the extracellular space can be neurotoxic. Intraneuronal Abeta42 accumulation is also associated with neurodegeneration. We reported previously that in Tg2576 amyloid precursor protein mutant transgenic mice, brain Abeta42 localized by immunoelectron microscopy to, and accumulated with aging in, the outer membranes of multivesicular bodies, especially in neuronal processes and synaptic compartments. We now demonstrate that primary neurons from Tg2576 mice recapitulate the in vivo localization and accumulation of Abeta42 with time in culture. Furthermore, we demonstrate that Abeta42 aggregates into oligomers within endosomal vesicles and along microtubules of neuronal processes, both in Tg2576 neurons with time in culture and in Tg2576 and human AD brain. These Abeta42 oligomer accumulations are associated with pathological alterations within processes and synaptic compartments in Tg2576 mouse and human AD brains.