Chin Jeannie, Massaro Catherine M, Palop Jorge J, Thwin Myo T, Yu Gui-Qiu, Bien-Ly Nga, Bender Aaron, Mucke Lennart
Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, California 94158, USA.
J Neurosci. 2007 Mar 14;27(11):2727-33. doi: 10.1523/JNEUROSCI.3758-06.2007.
Reelin regulates nervous system development and modulates synaptic plasticity in the adult brain. Several findings suggest that alterations in Reelin signaling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD). Cell surface receptors for Reelin, including integrins and very-low-density lipoprotein receptor/apolipoprotein E2 receptor, may be targets of amyloid-beta (Abeta) peptides presumed to play key roles in the pathogenesis of AD. Reelin also regulates the extent of tau phosphorylation. Finally, increased amounts of Reelin fragments have been found in CSF from AD patients, suggesting altered processing of Reelin. We therefore hypothesized that Reelin levels might be altered in the brains of human amyloid precursor protein (hAPP) transgenic mice, particularly in brain regions vulnerable to AD such as hippocampus and entorhinal cortex. Compared with nontransgenic controls, hAPP mice had significantly fewer Reelin-expressing pyramidal cells in the entorhinal cortex, the major population of glutamatergic neurons expressing Reelin in the brain. Western blot analysis of the hippocampus, which receives projections from the entorhinal cortex, revealed significant reductions in Reelin levels. In contrast, the number of Reelin-expressing GABAergic interneurons was not altered in either the entorhinal cortex or the hippocampus. Thus, neuronal expression of hAPP/Abeta is sufficient to reduce Reelin expression in a specific population of entorhinal cortical pyramidal neurons in vivo. Underscoring the relevance of these findings, we found qualitatively similar reductions of Reelin-expressing pyramidal neurons in the entorhinal cortex of AD brains. We conclude that alterations in Reelin processing or signaling may be involved in AD-related neuronal dysfunction.
Reelin调节神经系统发育并调节成年大脑中的突触可塑性。多项研究结果表明，Reelin信号通路的改变可能导致与阿尔茨海默病（AD）相关的神经元功能障碍。Reelin的细胞表面受体，包括整合素和极低密度脂蛋白受体/载脂蛋白E2受体，可能是淀粉样β（Aβ）肽的靶点，这些肽被认为在AD的发病机制中起关键作用。Reelin还调节tau蛋白磷酸化的程度。最后，在AD患者的脑脊液中发现了更多的Reelin片段，这表明Reelin的加工过程发生了改变。因此，我们推测在人类淀粉样前体蛋白（hAPP）转基因小鼠的大脑中，Reelin水平可能会发生改变，特别是在易受AD影响的脑区，如海马体和内嗅皮质。与非转基因对照组相比，hAPP小鼠内嗅皮质中表达Reelin的锥体细胞显著减少，内嗅皮质是大脑中表达Reelin的主要谷氨酸能神经元群体。对接受内嗅皮质投射的海马体进行蛋白质免疫印迹分析，结果显示Reelin水平显著降低。相比之下，在内嗅皮质或海马体中，表达Reelin的GABA能中间神经元的数量没有改变。因此，hAPP/Aβ的神经元表达足以在体内降低内嗅皮质特定锥体细胞群体中的Reelin表达。这些发现的相关性得到了强调，我们在AD大脑的内嗅皮质中发现了表达Reelin的锥体细胞在质量上有类似的减少。我们得出结论，Reelin加工或信号通路的改变可能与AD相关的神经元功能障碍有关。
