Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer’s disease–like (AD-like) neuropathology in the human brain. However, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively in noradrenergic neurons by monoamine oxidase A metabolism of norepinephrine, activated asparagine endopeptidase that cleaved Tau at residue N368 into aggregation- and propagation-prone forms, thus leading to LC degeneration and the spread of Tau pathology. Activation of asparagine endopeptidase–cleaved Tau aggregation in vitro and in intact cells was triggered by 3,4-dihydroxyphenylglycolaldehyde, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal that norepinephrine metabolism and Tau cleavage represent the specific molecular mechanism underlying the selective vulnerability of LC neurons in AD.

中文翻译：

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去甲肾上腺素代谢物DOPEGAL激活蓝绿色斑中的AEP和病理性Tau聚集

蓝斑脑（LC）中异常的Tau夹杂物是人脑中最早可检测到的阿尔茨海默氏病样（AD样）神经病理。然而，尚不清楚为何LC神经元选择性地易受Tau病理早期发展和疾病后期退化的困扰，以及LC是否可能将Tau病理学的定型传播播种到大脑的其他部位。在这里，我们显示3,4-二羟基苯乙醛（仅在去甲肾上腺素能神经元中由去甲肾上腺素的单胺氧化酶A代谢产生）激活了天冬酰胺内肽酶，该酶将残基N368的Tau裂解成易于聚集和传播的形式，从而导致LC变性和Tau病理学的传播。在体外和完整细胞中，天冬酰胺内肽酶切割的Tau聚集的激活是由3 4-二羟基苯基乙二醇醛，导致LC神经毒性并将病理传播到前脑。因此，我们的发现揭示了去甲肾上腺素的代谢和Tau裂解代表了AD中LC神经元选择性脆弱性的特定分子机制。