Noradrenergic sympathetic sprouting and cholinergic reinnervation maintains non-amyloidogenic processing of AβPP.
Noradrenergic sympathetic sprouting and cholinergic reinnervation maintains non-amyloidogenic processing of AβPP.
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DOI：
10.3233/jad-130608
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
McMahon LL
中科院分区：
文献类型：
--
作者：
Nelson AR;Kolasa K;McMahon LL
阿尔茨海默病（Alzheimer's disease，AD）以β淀粉样蛋白（amyloid-beta，Aβ）斑块、过度磷酸化的tau神经元缠结（hyperphosphorylated tau neurological tangles，NFT）和胆碱能功能障碍为特征。损伤内侧隔胆碱能神经元可模拟大鼠胆碱能变性。海马胆碱能去神经破坏神经生长因子（NGF）的逆行运输，导致其积累，随后触发去甲肾上腺素能交感神经纤维从上级颈神经节发芽到海马。以前，我们报告说，符合去甲肾上腺素能发芽是部分再神经支配的海马胆碱能纤维，和维护的M1 mAChR依赖的长期抑郁症在CA 3-CA 1突触，是失去了发芽的情况下。这些结果表明，交感神经发芽和伴随的胆碱能神经再支配维持M1 mAChR功能。有趣的是，去甲肾上腺素能交感神经和胆碱能发芽已被证明在AD死后人脑。此外，由于M1 mAChR在认知和淀粉样β蛋白前体（AβPP）的非淀粉样蛋白形成过程中的作用，其作为AD的治疗靶点已成为最近的焦点。在此，我们检验了一个假设，即去甲肾上腺素能交感神经发芽和相关的胆碱能神经支配增加维持了依赖于M1 mAChRs的非淀粉样蛋白生成AβPP加工。此外，我们研究了海马内Aβ42输注对去甲肾上腺素能交感神经和胆碱能发芽的影响。我们发现，Aβ42不仅对支配海马的中枢胆碱能纤维具有毒性，而且可以阻止和逆转去甲肾上腺素能交感神经发芽和伴随的胆碱能神经再支配。这些发现重申了发芽作为先天性代偿机制的临床意义，并强调了M1 mAChR作为AD治疗靶点的重要性。
Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) plaques, hyperphosphorylated tau neurofibrillary tangles (NFTs) and cholinergic dysfunction. Cholinergic degeneration can be mimicked in rats by lesioning cholinergic neurons in medial septum. Hippocampal cholinergic denervation disrupts retrograde transport of nerve growth factor (NGF), leading to its accumulation, which subsequently triggers sprouting of noradrenergic sympathetic fibers from the superior cervical ganglia into hippocampus. Previously we reported that coincident with noradrenergic sprouting is the partial reinnervation of hippocampus with cholinergic fibers, and the maintenance of a M1 mAChR dependent long-term depression at CA3-CA1 synapses that is lost in the absence of sprouting. These findings suggest that sympathetic sprouting and the accompanying cholinergic reinnervation maintains M1 mAChR function. Interestingly, noradrenergic sympathetic and cholinergic sprouting have been demonstrated in AD postmortem human brain. Furthermore, M1 mAChRs have been a recent focus as a therapeutic target for AD given their role in cognition and non-amyloidogenic processing of amyloid beta-protein precursor (AβPP). Here we tested the hypothesis that noradrenergic sympathetic sprouting and the associated increase in cholinergic innervation maintains non-amyloidogenic AβPP processing that is dependent upon M1 mAChRs. Also, we investigated the effect of intrahippocampal Aβ42 infusion on noradrenergic sympathetic and cholinergic sprouting. We found that Aβ42 is not only toxic to central cholinergic fibers innervating hippocampus but prevents and reverses noradrenergic sympathetic sprouting and the accompanying cholinergic reinnervation. These findings reiterate the clinical implications of sprouting as an innate compensatory mechanism and emphasize the importance of M1 mAChRs as an AD therapeutic target.
影响因子：
3.3
作者：
McCoy, P. A.;McMahon, L. L.
通讯作者：
McMahon, L. L.