Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease
Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease
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DOI：
10.1523/jneurosci.4218-08.2008
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发表时间：
2008-12-17
影响因子：
5.3
通讯作者：
Lee, Michael K.
中科院分区：
文献类型：
--
作者：
Liu, Ying;Yoo, Mi-Jeong;Lee, Michael K.
β-淀粉样蛋白（A β）病理学是阿尔茨海默病（AD）的基本致病成分。然而，A β病理学（包括A β沉积物/寡聚体和神经胶质反应）对神经变性的意义尚不清楚。特别是，尽管体外研究表明A β神经毒性，但具有显著A β沉积的小鼠模型缺乏前脑神经元的稳健和进行性损失。这样的结果助长了这样的观点，即A β病理学不足以在体内进行神经变性。在这项研究中，由于单胺能（MA能）神经元在AD的早期阶段显示退行性变化，我们研究了APPswe/PS1 Delta E9小鼠模型是否重现了AD病例中发生的进行性MA能神经变性。我们发现，在APPswe/PS1 Delta E9模型中前脑A β沉积的进展与前脑MA能传入神经的进展性损失相关。值得注意的是，轴突变性与细胞体的显著萎缩相关，并最终导致皮质下MA能神经元的大量丢失（类似于50%）。这些神经元的变性发生在皮质下部位没有明显的局部A β或tau病理学，并且在小鼠中焦虑相关行为的发作之前。我们的研究结果表明，A β病理转基因小鼠模型发展进行性MA能神经变性发生在AD病例。
beta-Amyloid (A beta) pathology is an essential pathogenic component in Alzheimer's disease (AD). However, the significance of A beta pathology, including A beta deposits/oligomers and glial reactions, to neurodegeneration is unclear. In particular, despite the A beta neurotoxicity indicated by in vitro studies, mouse models with significant A beta deposition lack robust and progressive loss of forebrain neurons. Such results have fueled the view that A beta pathology is insufficient for neurodegeneration in vivo. In this study, because monoaminergic (MAergic) neurons show degenerative changes at early stages of AD, we examined whether the APPswe/PS1 Delta E9 mouse model recapitulates progressive MAergic neurodegeneration occurring in AD cases. We show that the progression forebrain A beta deposition in the APPswe/PS1 Delta E9 model is associated with progressive losses of the forebrain MAergic afferents. Significantly, axonal degeneration is associated with significant atrophy of cell bodies and eventually leads to robust loss (similar to 50%) of subcortical MAergic neurons. Degeneration of these neurons occurs without obvious local A beta or tau pathology at the subcortical sites and precedes the onset of anxiety-associated behavior in the mice. Our results show that a transgenic mouse model of A beta pathology develops progressive MAergic neurodegeneration occurring in AD cases.