Cheng Fang, Fransson Lars-Åke, Mani Katrin
Department of Experimental Medical Science, Division of Neuroscience, Glycobiology Group, Lund University, Lund, Sweden.
J Neurochem. 2025 Jul;169(7):e70162. doi: 10.1111/jnc.70162.
In Alzheimer's disease (AD) there is accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (pTau) in the brain. Aβ activates kinases that phosphorylate tau. Increased pTau181 is a signal for hyperphosphorylation of tau. The generation of Aβ from amyloid precursor protein (APP) and the release of heparan sulfate (HS) from the proteoglycan glypican-1 (GPC1) are interconnected. Release of HS is APP-, ascorbate-, copper-, and NO-dependent. HS-Aβ interactions may regulate tau phosphorylation in human neural stem cells (NSC). The most influential risk factor for sporadic AD is the presence of the ε4 allele of apolipoprotein E (ApoE). Here, we have further explored the interplay between GPC1-derived HS and pTau181 formation in human neural progenitor cells (NPC) and induced neurons (iN) obtained by reprogramming of human fibroblasts from ApoE3- and ApoE4-carriers. HS release from GPC1 was either suppressed or stimulated, and effects on pTau181 were monitored by immunofluorescence microscopy and quantified by intensity measurements as well as by enzyme-linked immunosorbent assay (ELISA) technique. Stimulation of HS release decreased pTau181 in NSC but was without effect in NPC, where tau was mostly in the nuclei. However, suppression of HS release in NPC increased pTau181. Stimulation of HS release decreased pTau181 in ApoE4/4-iN but not in ApoE3/3-iN. A high intake of vitamin C may be of prophylactic value in ApoE4-positive individuals.
在阿尔茨海默病（AD）中，大脑中会出现β淀粉样蛋白（Aβ）的积累和tau蛋白的过度磷酸化（pTau）。Aβ激活使tau蛋白磷酸化的激酶。pTau181增加是tau蛋白过度磷酸化的一个信号。淀粉样前体蛋白（APP）产生Aβ与蛋白聚糖磷脂酰肌醇蛋白聚糖-1（GPC1）释放硫酸乙酰肝素（HS）是相互关联的。HS的释放依赖于APP、抗坏血酸、铜和一氧化氮。HS与Aβ的相互作用可能调节人类神经干细胞（NSC）中的tau蛋白磷酸化。散发性AD最具影响力的风险因素是载脂蛋白E（ApoE）的ε4等位基因的存在。在此，我们进一步探讨了来自ApoE3和ApoE4携带者的人类成纤维细胞重编程获得的人类神经祖细胞（NPC）和诱导神经元（iN）中GPC1衍生的HS与pTau181形成之间的相互作用。GPC1释放HS被抑制或刺激，并通过免疫荧光显微镜监测对pTau181的影响，并通过强度测量以及酶联免疫吸附测定（ELISA）技术进行定量。刺激HS释放可降低NSC中的pTau181，但对NPC无效，因为NPC中的tau蛋白大多位于细胞核中。然而，抑制NPC中HS的释放会增加pTau181。刺激HS释放可降低ApoE4/4-iN中的pTau181，但对ApoE3/3-iN无效。高剂量摄入维生素C可能对ApoE4阳性个体具有预防价值。
