Liu Ying, Yoo Mi-Jeong, Savonenko Alena, Stirling Wanda, Price Donald L, Borchelt David R, Mamounas Laura, Lyons W Ernest, Blue Mary E, Lee Michael K
Department of Pathology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
J Neurosci. 2008 Dec 17;28(51):13805-14. doi: 10.1523/JNEUROSCI.4218-08.2008.
beta-Amyloid (Abeta) pathology is an essential pathogenic component in Alzheimer's disease (AD). However, the significance of Abeta pathology, including Abeta deposits/oligomers and glial reactions, to neurodegeneration is unclear. In particular, despite the Abeta neurotoxicity indicated by in vitro studies, mouse models with significant Abeta deposition lack robust and progressive loss of forebrain neurons. Such results have fueled the view that Abeta 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/PS1DeltaE9 mouse model recapitulates progressive MAergic neurodegeneration occurring in AD cases. We show that the progression forebrain Abeta deposition in the APPswe/PS1DeltaE9 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 (approximately 50%) of subcortical MAergic neurons. Degeneration of these neurons occurs without obvious local Abeta 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 Abeta pathology develops progressive MAergic neurodegeneration occurring in AD cases.
β-淀粉样蛋白（Aβ）病理是阿尔茨海默病（AD）的一个重要致病成分。然而，Aβ病理，包括Aβ沉积/寡聚体和胶质细胞反应，对神经退行性变的意义尚不清楚。特别是，尽管体外研究表明Aβ具有神经毒性，但具有显著Aβ沉积的小鼠模型缺乏前脑神经元的强烈且进行性丧失。这些结果助长了一种观点，即Aβ病理不足以导致体内神经退行性变。在本研究中，由于单胺能（MA能）神经元在AD早期显示出退行性变化，我们研究了APPswe/PS1DeltaE9小鼠模型是否重现了AD病例中发生的进行性MA能神经退行性变。我们发现，APPswe/PS1DeltaE9模型中前脑Aβ沉积的进展与前脑MA能传入纤维的进行性丧失有关。值得注意的是，轴突退变与细胞体的显著萎缩相关，并最终导致皮质下MA能神经元的大量丧失（约50%）。这些神经元的退变在皮质下部位没有明显的局部Aβ或tau病理改变的情况下发生，且先于小鼠出现焦虑相关行为。我们的结果表明，Aβ病理的转基因小鼠模型发生了AD病例中出现的进行性MA能神经退行性变。
