Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39208, USA.
Curr Alzheimer Res. 2012 May;9(4):473-80. doi: 10.2174/156720512800492567.
More than a third of Alzheimer's disease (AD) patients show nigrostriatal pathway disturbances, resulting in akinesia (inability to initiate movement) and bradykinesia (slowness of movement). The high prevalence of this dysfunction of dopaminergic neuron in the nigrostriatal pathway in AD suggests that the risk factors for AD appear also significant risk factors for substantia nigra pars compacta (SNpc) lesions. Previously, we have demonstrated that allopregnanolone (APα) promotes neurogenesis and improves the cognitive function in a triple transgenic mouse model of AD (3xTgAD). In this study, we sought to exam 1) the SNpc lesions in 3xTgAD mice and 2) the impact of APα on promoting the regeneration of new dopaminergic neurons in SNpc of the 3xTgAD mice. The number of Nissl-stained total neurons, tyrosine hydroxylase (TH) positive neurons, and BrdU/TH double positive newly formed neurons were analyzed with unbiased stereology. In the SNpc of 3xTgAD mice, TH positive neurons was 47+- 18 % (p = 0.007), total neurons was 62 +-11.6 % (p = 0.016), of those in the SNpc of non-Tg mice, respectively. APα treatment increased the TH positive neurons in the SNpc of 3xTgAD mice to 93.2 +- 18.5 (p = 0.021 vs. 3xTgAD vehicle) and the total neurons to 84.9+- 6.6 (p = 0.046 vs. 3xTgAD vehicle) of non-Tg mice. These findings indicate that there is a loss of neurons, specifically the TH positive neurons in SNpc of 3xTgAD mice, and that APα reverses the lesion in SNpc of 3xTgAD by increasing the formation of new TH neurons.
超过三分之一的阿尔茨海默病（AD）患者表现出黑质纹状体通路紊乱，导致运动不能（无法启动运动）和运动迟缓（运动缓慢）。AD 中黑质纹状体通路中多巴胺能神经元这种功能障碍的高患病率表明，AD 的风险因素也明显是黑质致密部（SNpc）病变的危险因素。以前，我们已经证明了别孕烯醇酮（APα）可促进神经发生并改善 AD 三转基因小鼠模型（3xTgAD）的认知功能。在这项研究中，我们试图检查 1）3xTgAD 小鼠中的 SNpc 病变，以及 2）APα 对促进 3xTgAD 小鼠 SNpc 中新的多巴胺能神经元再生的影响。用无偏立体学分析 Nissl 染色的总神经元、酪氨酸羟化酶（TH）阳性神经元和 BrdU/TH 双阳性新形成神经元的数量。在 3xTgAD 小鼠的 SNpc 中，TH 阳性神经元为 47+-18%（p=0.007），总神经元为 62+-11.6%（p=0.016），而非 Tg 小鼠的 SNpc 中分别为。APα 处理可使 3xTgAD 小鼠的 SNpc 中 TH 阳性神经元增加到 93.2+-18.5（p=0.021 与 3xTgAD 载体相比），总神经元增加到 84.9+-6.6（p=0.046 与 3xTgAD 载体相比），非 Tg 小鼠。这些发现表明，3xTgAD 小鼠的 SNpc 中存在神经元，特别是 TH 阳性神经元的丧失，并且 APα 通过增加新的 TH 神经元的形成来逆转 3xTgAD 中的病变。
