Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael St. Whitehead BLDG Room #141, Atlanta, GA, 30322, USA.
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, USA.
Acta Neuropathol. 2021 Jul;142(1):139-158. doi: 10.1007/s00401-021-02315-1. Epub 2021 Apr 25.
ApoE4 enhances Tau neurotoxicity and promotes the early onset of AD. Pretangle Tau in the noradrenergic locus coeruleus (LC) is the earliest detectable AD-like pathology in the human brain. However, a direct relationship between ApoE4 and Tau in the LC has not been identified. Here we show that ApoE4 selectively binds to the vesicular monoamine transporter 2 (VMAT2) and inhibits neurotransmitter uptake. The exclusion of norepinephrine (NE) from synaptic vesicles leads to its oxidation into the toxic metabolite 3,4-dihydroxyphenyl glycolaldehyde (DOPEGAL), which subsequently activates cleavage of Tau at N368 by asparagine endopeptidase (AEP) and triggers LC neurodegeneration. Our data reveal that ApoE4 boosts Tau neurotoxicity via VMAT2 inhibition, reduces hippocampal volume, and induces cognitive dysfunction in an AEP- and Tau N368-dependent manner, while conversely ApoE3 binds Tau and protects it from cleavage. Thus, ApoE4 exacerbates Tau neurotoxicity by increasing VMAT2 vesicle leakage and facilitating AEP-mediated Tau proteolytic cleavage in the LC via DOPEGAL.
载脂蛋白 E4 增强 Tau 神经毒性并促进 AD 的早期发病。去神经原性蓝斑核（LC）中的 Tau 预缠结是人类大脑中最早可检测到的类似 AD 的病理学改变。然而，ApoE4 与 LC 中的 Tau 之间的直接关系尚未确定。在这里，我们表明 ApoE4 选择性地结合囊泡单胺转运体 2（VMAT2）并抑制神经递质摄取。去甲肾上腺素（NE）从突触小泡中排出会导致其氧化成有毒代谢物 3,4-二羟基苯乙二醇醛（DOPEGAL），随后 DOPEGAL 激活天冬酰胺内肽酶（AEP）切割 Tau 上的 N368，引发 LC 神经退行性变。我们的数据表明，ApoE4 通过 VMAT2 抑制增强 Tau 神经毒性，减少海马体积，并以 AEP 和 Tau N368 依赖性方式引起认知功能障碍，而相反，ApoE3 结合 Tau 并防止其裂解。因此，ApoE4 通过增加 VMAT2 囊泡渗漏并通过 DOPEGAL 促进 AEP 介导的 Tau 蛋白水解切割来加剧 Tau 神经毒性。
