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Neuronal spreading and plaque induction of intracellular Aβ and its disruption of Aβ homeostasis
Acta Neuropathologica ( IF 9.3 ) Pub Date : 2021-07-16 , DOI: 10.1007/s00401-021-02345-9
Tomas T Roos 1 , Megg G Garcia 1, 2 , Isak Martinsson 1 , Rana Mabrouk 3 , Bodil Israelsson 1 , Tomas Deierborg 2 , Asgeir Kobro-Flatmoen 4 , Heikki Tanila 3 , Gunnar K Gouras 1
Affiliation  

The amyloid-beta peptide (Aβ) is thought to have prion-like properties promoting its spread throughout the brain in Alzheimer’s disease (AD). However, the cellular mechanism(s) of this spread remains unclear. Here, we show an important role of intracellular Aβ in its prion-like spread. We demonstrate that an intracellular source of Aβ can induce amyloid plaques in vivo via hippocampal injection. We show that hippocampal injection of mouse AD brain homogenate not only induces plaques, but also damages interneurons and affects intracellular Aβ levels in synaptically connected brain areas, paralleling cellular changes seen in AD. Furthermore, in a primary neuron AD model, exposure of picomolar amounts of brain-derived Aβ leads to an apparent redistribution of Aβ from soma to processes and dystrophic neurites. We also observe that such neuritic dystrophies associate with plaque formation in AD-transgenic mice. Finally, using cellular models, we propose a mechanism for how intracellular accumulation of Aβ disturbs homeostatic control of Aβ levels and can contribute to the up to 10,000-fold increase of Aβ in the AD brain. Our data indicate an essential role for intracellular prion-like Aβ and its synaptic spread in the pathogenesis of AD.



中文翻译:

细胞内 Aβ 的神经元扩散和斑块诱导及其对 Aβ 稳态的破坏

淀粉样蛋白-β 肽 (Aβ) 被认为具有类似朊病毒的特性,可促进其在阿尔茨海默病 (AD) 中在整个大脑中的传播。然而,这种传播的细胞机制仍不清楚。在这里,我们展示了细胞内 Aβ 在其朊病毒样传播中的重要作用。我们证明 Aβ 的细胞内来源可以通过海马注射在体内诱导淀粉样蛋白斑块。我们表明,小鼠 AD 脑匀浆的海马注射不仅会诱导斑块,还会损害中间神经元并影响突触连接的大脑区域的细胞内 Aβ 水平,与 AD 中观察到的细胞变化平行。此外,在原代神经元 AD 模型中,皮摩尔量的脑源性 Aβ 的暴露导致 Aβ 从体细胞明显重新分布到突起和营养不良的神经突。我们还观察到这种神经炎性营养不良与 AD 转基因小鼠的斑块形成有关。最后,使用细胞模型,我们提出了一种机制,即 Aβ 的细胞内积累如何干扰 Aβ 水平的稳态控制,并有助于 AD 大脑中 Aβ 增加高达 10,000 倍。我们的数据表明细胞内朊病毒样 Aβ 及其突触扩散在 AD 发病机制中的重要作用。

更新日期:2021-07-18
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