Iannitelli Alexa F, Hassanein Leslie, Tish Margaret M, Mulvey Bernard, Blankenship Harris E, Korukonda Anu, Liles L Cameron, Sharpe Amanda L, Pare Jean-Francoise, Villalba Rosa, Segal Arielle, Sloan Steven A, Martinowich Keri, Dougherty Joseph D, McCann Katharine E, Smith Yoland, Beckstead Michael J, Weinshenker David
bioRxiv. 2025 Apr 5:2023.03.07.530845. doi: 10.1101/2023.03.07.530845.
The locus coeruleus (LC), the major source of norepinephrine (NE) in the brain, is among the earliest site of pathology in both Alzheimer's disease (AD) and Parkinson's disease (PD), and it undergoes catastrophic degeneration later in both disorders. Dysregulation of the LC is thought to contribute to prodromal symptoms of AD and PD such as anxiety and sleep disturbances, while frank LC loss promotes cognitive decline. However, the mechanisms responsible for its selective vulnerability are unknown. It has been suggested that neuromelanin (NM) pigment contributes to LC susceptibility, but causal relationships have been difficult to test because rodents do not naturally produce NM. Here, we report that viral-mediated expression of human tyrosinase induced pigmentation in mouse LC neurons that recapitulated key features of natural primate NM. One week of NM accumulation resulted in LC neuron hyperactivity, reduced tissue NE levels, transcriptional changes, and anxiety-like behavior. By 6-10 weeks, NM accumulation was associated with severe LC neuron neurodegeneration and microglial engulfment of the pigment granules, while the anxiety-like behavior abated. These phenotypes are reminiscent of LC dysfunction and cell death in AD and PD, validating this model for studying the consequences of NM accumulation in the LC as it relates to neurodegenerative disease.
Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common neurodegenerative diseases worldwide. Because therapies that cure or even prevent their progression are lacking, research is focused on the identifying earliest signs of disease as targets for diagnosis and treatment. The locus coeruleus (LC), the main source of the neurotransmitter n norepinephrine (NE) in the brain, is one of the first brain regions affected in both AD and PD. LC dysregulation promotes prodromal AD and PD symptoms, while its degeneration accelerates disease progression. Here we identify neuromelanin (NM) pigment as a LC vulnerability factor that induces neuronal hyperactivity followed by cell death. Approaches that mitigate NM accumulation and toxicity may target the earliest phases of neurodegenerative disease.
蓝斑（LC）是大脑中去甲肾上腺素（NE）的主要来源，是阿尔茨海默病（AD）和帕金森病（PD）最早出现病理变化的部位之一，并且在这两种疾病后期都会发生灾难性退变。蓝斑功能失调被认为会导致AD和PD的前驱症状，如焦虑和睡眠障碍，而蓝斑的明显缺失会促进认知能力下降。然而，其选择性易损性的机制尚不清楚。有人提出神经黑色素（NM）色素会导致蓝斑易感性增加，但由于啮齿动物不会自然产生NM，因此因果关系难以验证。在此，我们报告病毒介导的人类酪氨酸酶表达可诱导小鼠蓝斑神经元色素沉着，重现了天然灵长类动物神经黑色素的关键特征。一周的神经黑色素积累导致蓝斑神经元活动亢进、组织去甲肾上腺素水平降低、转录变化以及类似焦虑的行为。到6 - 10周时，神经黑色素积累与严重的蓝斑神经元神经退行性变和小胶质细胞对色素颗粒的吞噬有关，而类似焦虑的行为有所减轻。这些表型让人联想到AD和PD中蓝斑功能障碍和细胞死亡，验证了该模型可用于研究神经黑色素在蓝斑中积累与神经退行性疾病相关的后果。
阿尔茨海默病（AD）和帕金森病（PD）是全球最常见的两种神经退行性疾病。由于缺乏治愈甚至预防其进展的疗法，研究重点在于识别疾病的最早迹象作为诊断和治疗靶点。蓝斑（LC）是大脑中神经递质去甲肾上腺素（NE）的主要来源，是AD和PD中最早受影响的脑区之一。蓝斑功能失调会促进AD和PD的前驱症状，而其退变会加速疾病进展。在此我们确定神经黑色素（NM）色素是蓝斑易损性因素，可诱导神经元活动亢进，随后导致细胞死亡。减轻神经黑色素积累和毒性的方法可能针对神经退行性疾病的最早阶段。
