Vanherle Sarah, Janssen Art, Gutiérrez de Ravé Manuel, Janssen Bieke, Lodder Chritica, Botella Lucena Pablo, Kessels Sofie, Hardy Jana, Vandeput Eline, Wang Yanyan, Stancu Ilie-Cosmin, Segal Andrei, Kleinewietfeld Markus, Voets Thomas, Brône Bert, Poovathingal Suresh, Alpizar Yeranddy A, Dewachter Ilse
Department of Neurosciences, Biomedical Research Institute BIOMED, Hasselt University, Hasselt, Belgium.
Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Mol Psychiatry. 2025 Apr 30. doi: 10.1038/s41380-025-03036-7.
In AD, amyloid pathology (A) precedes progressive development of tau pathology (T) and neurodegeneration (N), with the latter (T/N) processes associated with symptom progression. Recent anti-amyloid beta (Aβ) clinical trials raise hope but indicate the need for multi-targeted therapies, to effectively halt clinical AD and ATN pathology progression. APOE-related putative protective mutations (including APOE3Christchurch, RELN-COLBOS) were recently identified in case reports with exceptionally high resilience to autosomal dominant AD. In these cases, Nature provided proof of concept for halting autosomal dominant AD and ATN progression in humans, despite a high amyloid load, and pointing to the APOE pathway as a potential target. This is further supported by the recent identification of APOE4 homozygosity as genetic AD. Here we studied the role of APOE in a preclinical model that robustly mimics amyloid-facilitated (A) tau pathology (T) and subsequent neurodegeneration (N), denoted as ATN model, generated by crossing 5xFAD (F ) and TauP301S (T ) mice. We show that APOE deficiency, markedly inhibited progression to tau pathology and tau-induced neurodegeneration in this ATN model, despite a high Aβ load, reminiscent of the high resilience ADAD case reports. Further study identified, despite increased Aβ load (W02 stained), a significant decrease in compacted, dense core plaques stained by ThioS in APOE deficient ATN mice. Furthermore, single-cell RNA sequencing (scRNA-seq) showed a crucial role of APOE in microglial conversion beyond homeostatic microglia to reactive and disease associated microglia (DAM) in this ATN preclinical model. Microglial elimination significantly decreased amyloid-driven tau pathology, in the presence of APOE, but not in APOE deficient mice. Together the data demonstrate that APOE deficiency inhibits amyloid-driven tau pathology and subsequent neurodegeneration, by pleiotropic effects including prevention of dense core plaque formation and halting conversion of homeostatic microglia. We here present a model recapitulating inhibition of amyloid-facilitated tau pathology by APOE deficiency despite high Aβ load, important for understanding the role of APOE, and APOE-dependent processes in ATN progression and its therapeutic exploitation in AD.
在阿尔茨海默病（AD）中，淀粉样蛋白病变（A）先于tau蛋白病变（T）和神经退行性变（N）的渐进发展，而后两者（T/N）过程与症状进展相关。近期抗淀粉样蛋白β（Aβ）的临床试验带来了希望，但也表明需要多靶点治疗，以有效阻止临床AD和ATN病变的进展。在常染色体显性AD具有极高恢复力的病例报告中，最近发现了与载脂蛋白E（APOE）相关的假定保护性突变（包括APOE3克赖斯特彻奇突变、RETN-COLBOS突变）。在这些病例中，尽管淀粉样蛋白负荷很高，但大自然提供了在人类中阻止常染色体显性AD和ATN进展的概念验证，并指出APOE途径是一个潜在靶点。最近将APOE4纯合性鉴定为遗传性AD进一步支持了这一点。在此，我们在一个临床前模型中研究了APOE的作用，该模型通过将5xFAD（F）小鼠和TauP301S（T）小鼠杂交构建，能有力地模拟淀粉样蛋白促进的（A）tau蛋白病变（T）及随后的神经退行性变（N）（称为ATN模型）。我们发现，在这个ATN模型中，尽管Aβ负荷很高，但APOE缺乏显著抑制了向tau蛋白病变和tau蛋白诱导的神经退行性变的进展，这让人想起了常染色体显性AD具有高恢复力的病例报告。进一步研究发现，尽管Aβ负荷增加（W02染色），但在APOE缺乏的ATN小鼠中，硫黄素S染色的紧密、致密核心斑块显著减少。此外，单细胞RNA测序（scRNA-seq）表明，在这个ATN临床前模型中，APOE在小胶质细胞从稳态小胶质细胞向反应性和疾病相关小胶质细胞（DAM）的转变中起关键作用。在有APOE存在的情况下，清除小胶质细胞显著减少了淀粉样蛋白驱动的tau蛋白病变，但在APOE缺乏的小鼠中则不然。这些数据共同表明，APOE缺乏通过多效性作用抑制淀粉样蛋白驱动的tau蛋白病变及随后的神经退行性变，这些作用包括防止致密核心斑块形成以及阻止稳态小胶质细胞的转变。我们在此提出一个模型，该模型概括了尽管Aβ负荷很高，但APOE缺乏对淀粉样蛋白促进的tau蛋白病变的抑制作用，这对于理解APOE的作用以及APOE依赖性过程在ATN进展中的作用及其在AD治疗中的应用很重要。
