Naylor Jennifer C, Kilts Jason D, Hulette Christine M, Steffens David C, Blazer Dan G, Ervin John F, Strauss Jennifer L, Allen Trina B, Massing Mark W, Payne Victoria M, Youssef Nagy A, Shampine Lawrence J, Marx Christine E
VA Mid-Atlantic Mental Illness, Research and Clinical Center (MIRECC), Durham, NC, USA.
Biochim Biophys Acta. 2010 Aug;1801(8):951-9. doi: 10.1016/j.bbalip.2010.05.006. Epub 2010 May 19.
The neurosteroid allopregnanolone has pronounced neuroprotective actions, increases myelination, and enhances neurogenesis. Evidence suggests that allopregnanolone dysregulation may play a role in the pathophysiology of Alzheimer's disease (AD) and other neurodegenerative disorders. Our prior data demonstrate that allopregnanolone is reduced in prefrontal cortex in male patients with AD compared to male cognitively intact control subjects, and inversely correlated with neuropathological disease stage (Braak and Braak). We therefore determined if allopregnanolone levels are also reduced in AD patients compared to control subjects in temporal cortex, utilizing a larger set of samples from both male and female patients. In addition, we investigated if neurosteroids are altered in subjects who are APOE4 allele carriers. Allopregnanolone, dehydroepiandrosterone (DHEA), and pregnenolone levels were determined in temporal cortex postmortem samples by gas chromatography/mass spectrometry, preceded by high performance liquid chromatography (40 subjects with AD/41 cognitively intact control subjects). Allopregnanolone levels are reduced in temporal cortex in patients with AD (median 2.68 ng/g, n=40) compared to control subjects (median 5.64 ng/g, n=41), Mann-Whitney p=0.0002, and inversely correlated with Braak and Braak neuropathological disease stage (Spearman r=-0.38, p=0.0004). DHEA and pregnenolone are increased in patients with AD compared to control subjects. Patients carrying an APOE4 allele demonstrate reduced allopregnanolone levels in temporal cortex (Mann-Whitney p=0.04). In summary, our findings indicate that neurosteroids are altered in temporal cortex in patients with AD and related to neuropathological disease stage. In addition, the APOE4 allele is associated with reduced allopregnanolone levels. Neurosteroids may be relevant to the neurobiology and therapeutics of AD.
神经甾体别孕烯醇酮具有显著的神经保护作用，可增加髓鞘形成并促进神经发生。有证据表明，别孕烯醇酮失调可能在阿尔茨海默病（AD）和其他神经退行性疾病的病理生理学中起作用。我们之前的数据表明，与认知功能正常的男性对照受试者相比，AD男性患者前额叶皮质中的别孕烯醇酮水平降低，且与神经病理学疾病阶段（Braak和Braak分期）呈负相关。因此，我们利用来自更多男性和女性患者的样本，确定与对照受试者相比，AD患者颞叶皮质中的别孕烯醇酮水平是否也降低。此外，我们研究了携带APOE4等位基因的受试者的神经甾体是否发生改变。通过气相色谱/质谱法测定死后颞叶皮质样本中的别孕烯醇酮、脱氢表雄酮（DHEA）和孕烯醇酮水平，测定前先进行高效液相色谱分析（40例AD患者/41例认知功能正常的对照受试者）。与对照受试者（中位数5.64 ng/g，n = 41）相比，AD患者颞叶皮质中的别孕烯醇酮水平降低（中位数2.68 ng/g，n = 40），Mann-Whitney检验p = 0.0002，且与Braak和Braak神经病理学疾病阶段呈负相关（Spearman相关系数r = -0.38，p = 0.0004）。与对照受试者相比，AD患者的DHEA和孕烯醇酮水平升高。携带APOE4等位基因的患者颞叶皮质中的别孕烯醇酮水平降低（Mann-Whitney检验p = 0.04）。总之，我们的研究结果表明，AD患者颞叶皮质中的神经甾体发生改变，且与神经病理学疾病阶段相关。此外，APOE4等位基因与别孕烯醇酮水平降低有关。神经甾体可能与AD的神经生物学和治疗方法相关。
