Animal and Avian Sciences Department, University of Maryland, College Park, MD, USA.
Myriad Neuroscience (Assurex Health), Mason, OH, USA (present address).
J Alzheimers Dis. 2019;68(1):115-126. doi: 10.3233/JAD-180487.
The degeneration in the locus coeruleus associated with Alzheimer's disease suggests an involvement of the noradrenergic system in the disease pathogenesis. The role of depleted norepinephrine was tested in adult and aged rhesus macaques to develop a potential model for testing Alzheimer's disease interventions. Monkeys were injected with the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or vehicle at 0, 3, and 6 months; brains were harvested at 9 months. Reduced norepinephrine in the locus coeruleus was accompanied by decreased dopamine β-hydroxylase staining and increased amyloid-β load in the aged group, and the proportion of potentially toxic amyloid-β42 peptide was increased. Immunohistochemistry revealed no effects on microglia or astrocytes. DSP4 treatment altered amyloid processing, but these changes were not associated with the induction of chronic neuroinflammation. These findings suggest norepinephrine deregulation is an essential component of a nonhuman primate model of Alzheimer's disease, but further refinement is necessary.
与阿尔茨海默病相关的蓝斑退化表明去甲肾上腺素能系统参与了疾病的发病机制。为了开发一种用于测试阿尔茨海默病干预措施的潜在模型，我们在成年和老年恒河猴中测试了去甲肾上腺素耗竭的作用。猴子在 0、3 和 6 个月时接受去甲肾上腺素能神经毒素 N-(2-氯乙基)-N-乙基-2-溴苯甲胺（DSP4）或载体注射；9 个月时收获大脑。在老年组中，蓝斑内去甲肾上腺素减少伴随着多巴胺β-羟化酶染色减少和淀粉样蛋白-β负荷增加，潜在毒性淀粉样蛋白-β42 肽的比例增加。免疫组织化学显示小胶质细胞或星形胶质细胞没有变化。DSP4 处理改变了淀粉样蛋白的处理，但这些变化与慢性神经炎症的诱导无关。这些发现表明，去甲肾上腺素能失调是阿尔茨海默病非人类灵长类动物模型的一个重要组成部分，但需要进一步改进。
