Departments of Human Genetics and.
Neurology, Emory University, Atlanta, Georgia 30322.
J Neurosci. 2018 Jan 3;38(1):74-92. doi: 10.1523/JNEUROSCI.1483-17.2017. Epub 2017 Nov 13.
The brainstem locus coeruleus (LC) supplies norepinephrine to the forebrain and degenerates in Alzheimer's disease (AD). Loss of LC neurons is correlated with increased severity of other AD hallmarks, including β-amyloid (Aβ) plaques, tau neurofibrillary tangles, and cognitive deficits, suggesting that it contributes to the disease progression. Lesions of the LC in amyloid-based transgenic mouse models of AD exacerbate Aβ pathology, neuroinflammation, and cognitive deficits, but it is unknown how the loss of LC neurons affects tau-mediated pathology or behavioral abnormalities. Here we investigate the impact of LC degeneration in a mouse model of tauopathy by lesioning the LC of male and female P301S tau transgenic mice with the neurotoxin N-(2-chloroethyl)ethyl-bromobenzylamine (DSP-4) starting at 2 months of age. By 6 months, deficits in hippocampal-dependent spatial (Morris water maze) and associative (contextual fear conditioning) memory were observed in lesioned P301S mice while performance remained intact in all other genotype and treatment groups, indicating that tau and LC degeneration act synergistically to impair cognition. By 10 months, the hippocampal neuroinflammation and neurodegeneration typically observed in unlesioned P301S mice were exacerbated by DSP-4, and mortality was also accelerated. These DSP-4-induced changes were accompanied by only a mild aggravation of tau pathology, suggesting that increased tau burden cannot fully account for the effects of LC degeneration. Combined, these experiments demonstrate that loss of LC noradrenergic neurons exacerbates multiple phenotypes caused by pathogenic tau, and provides complementary data to highlight the dual role LC degeneration has on both tau and Aβ pathologies in AD. Elucidating the mechanisms underlying AD is crucial to developing effective diagnostics and therapeutics. The degeneration of the LC and loss of noradrenergic transmission have been recognized as ubiquitous events in AD pathology, and previous studies demonstrated that LC lesions exacerbate pathology and cognitive deficits in amyloid-based mouse models. Here, we reveal a complementary role of LC degeneration on tau-mediated aspects of the disease by using selective lesions of the LC and the noradrenergic system to demonstrate an exacerbation of cognitive deficits, neuroinflammation, neurodegeneration in a transgenic mouse model of tauopathy. Our data support an integral role for the LC in modulating the severity of both canonical AD-associated pathologies, as well as the detrimental consequences of LC degeneration during disease progression.
脑桥蓝斑（LC）将去甲肾上腺素供应到前脑，并在阿尔茨海默病（AD）中退化。LC 神经元的丧失与其他 AD 标志物的严重程度增加相关，包括 β-淀粉样蛋白（Aβ）斑块、tau 神经原纤维缠结和认知缺陷，表明其有助于疾病进展。AD 淀粉样蛋白基础转基因小鼠模型中 LC 的损伤加剧了 Aβ 病理学、神经炎症和认知缺陷，但尚不清楚 LC 神经元的丧失如何影响 tau 介导的病理学或行为异常。在这里，我们通过在 2 个月大时用神经毒素 N-（2-氯乙基）乙基-溴苄胺（DSP-4）对雄性和雌性 P301S tau 转基因小鼠进行 LC 损伤，研究了 LC 退化对 tau 病模型的影响。到 6 个月时，损伤的 P301S 小鼠表现出海马依赖性空间（莫里斯水迷宫）和联想（情境恐惧条件反射）记忆缺陷，而所有其他基因型和治疗组的表现仍然完整，表明 tau 和 LC 退化协同作用损害认知。到 10 个月时，未损伤的 P301S 小鼠中通常观察到的海马神经炎症和神经退行性变被 DSP-4 加剧，死亡率也加速。这些由 DSP-4 引起的变化伴随着 tau 病理学的轻微加重，表明 tau 负担的增加不能完全解释 LC 退化的影响。综合来看，这些实验表明，LC 去甲肾上腺素能神经元的丧失加剧了致病性 tau 引起的多种表型，并提供了补充数据来强调 LC 退化对 AD 中 tau 和 Aβ 病理学的双重作用。阐明 AD 的发病机制对于开发有效的诊断和治疗方法至关重要。LC 退化和去甲肾上腺素能传递的丧失已被认为是 AD 病理学中的普遍事件，先前的研究表明，LC 损伤加剧了淀粉样蛋白基础小鼠模型中的病理学和认知缺陷。在这里，我们通过使用选择性 LC 损伤和去甲肾上腺素能系统来揭示 LC 退化在 tau 介导的疾病方面的互补作用，证明了在 tau 病转基因小鼠模型中认知缺陷、神经炎症、神经退行性变的加剧。我们的数据支持 LC 在调节两种典型 AD 相关病理学的严重程度以及在疾病进展过程中 LC 退化的不利后果方面的重要作用。
