Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, A1B 3V6, Canada.
Department of Psychology, Faculty of Science, Memorial University of Newfoundland, St. John's, NL, A1B 3X9, Canada.
Alzheimers Res Ther. 2019 Jul 3;11(1):59. doi: 10.1186/s13195-019-0511-2.
The earliest brain pathology related to Alzheimer's disease (AD) is hyperphosphorylated soluble tau in the noradrenergic locus coeruleus (LC) neurons. Braak characterizes five pretangle tau stages preceding AD tangles. Pretangles begin in young humans and persist in the LC while spreading from there to other neuromodulatory neurons and, later, to the cortex. While LC pretangles appear in all by age 40, they do not necessarily result in AD prior to death. However, with age and pretangle spread, more individuals progress to AD stages. LC neurons are lost late, at Braak stages III-IV, when memory deficits appear. It is not clear if LC hyperphosphorylated tau generates the pathology and cognitive changes associated with preclinical AD. We use a rat model expressing pseudohyperphosphorylated human tau in LC to investigate the hypothesis that LC pretangles generate preclinical Alzheimer pathology.
We infused an adeno-associated viral vector carrying a human tau gene pseudophosphorylated at 14 sites common in LC pretangles into 2-3- or 14-16-month TH-Cre rats. We used odor discrimination to probe LC dysfunction, and we evaluated LC cell and fiber loss.
Abnormal human tau was expressed in LC and exhibited somatodendritic mislocalization. In rats infused at 2-3 months old, 4 months post-infusion abnormal LC tau had transferred to the serotonergic raphe neurons. After 7 months, difficult similar odor discrimination learning was impaired. Impairment was associated with reduced LC axonal density in the olfactory cortex and upregulated β1-adrenoceptors. LC infusions in 14-16-month-old rats resulted in more severe outcomes. By 5-6 months post-infusion, rats were impaired even in simple odor discrimination learning. LC neuron number was reduced. Human tau appeared in the microglia and cortical neurons.
Our animal model suggests, for the first time, that Braak's hypothesis that human AD originates with pretangle stages is plausible. LC pretangle progression here generates both preclinical AD pathological changes and cognitive decline. The odor discrimination deficits are similar to human odor identification deficits seen with aging and preclinical AD. When initiated in aged rats, pretangle stages progress rapidly and cause LC cell loss. These age-related outcomes are associated with a severe learning impairment consistent with memory decline in Braak stages III-IV.
与阿尔茨海默病（AD）相关的最早的脑病理学改变是去甲肾上腺素能蓝斑核（LC）神经元中过度磷酸化的可溶性tau。Braak 将 AD 缠结之前的五个 tau 前缠结阶段进行了特征描述。前缠结始于年轻人，并在 LC 中持续存在，然后从那里扩散到其他神经调节神经元，随后扩散到皮质。虽然 LC 前缠结在 40 岁之前出现在所有人中，但它们在死亡前不一定会导致 AD。然而，随着年龄的增长和前缠结的扩散，更多的人会进展到 AD 阶段。当记忆缺陷出现时，LC 神经元在 Braak 阶段 III-IV 中丢失。目前尚不清楚 LC 过度磷酸化 tau 是否会产生与临床前 AD 相关的病理学和认知变化。我们使用一种在 LC 中表达假过度磷酸化人 tau 的大鼠模型来研究以下假设，即 LC 前缠结产生临床前 AD 病理学。
我们将携带在 LC 前缠结中常见的 14 个位点假磷酸化的人 tau 基因的腺相关病毒载体注入 2-3 个月或 14-16 个月龄的 TH-Cre 大鼠中。我们使用气味辨别来探测 LC 功能障碍，并评估 LC 细胞和纤维丢失。
异常的人 tau 在 LC 中表达，并表现出树突体定位异常。在 2-3 个月龄大鼠中进行 LC 输注，输注后 4 个月异常 LC tau 已转移到 5-羟色胺能中缝核神经元。7 个月后，难以进行类似的气味辨别学习受到损害。损伤与嗅皮质 LC 轴突密度降低和β1-肾上腺素受体上调有关。在 14-16 个月龄大鼠中进行 LC 输注会导致更严重的后果。输注后 5-6 个月，即使是简单的气味辨别学习，大鼠也受到损害。LC 神经元数量减少。人 tau 出现在小胶质细胞和皮质神经元中。
我们的动物模型首次表明，Braak 的假设即 AD 起源于前缠结阶段是合理的。LC 前缠结的进展在此产生了临床前 AD 病理变化和认知下降。气味辨别缺陷类似于与衰老和临床前 AD 相关的人类气味识别缺陷。当在老年大鼠中启动时，前缠结阶段迅速进展并导致 LC 细胞丢失。这些与年龄相关的结果与 Braak 阶段 III-IV 中的记忆衰退一致，与严重的学习障碍有关。
