APOE deficiency inhibits amyloid-facilitated (A) tau pathology (T) and neurodegeneration (N), halting progressive ATN pathology in a preclinical model

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Sarah Vanherle, Art Janssen, Manuel Gutiérrez de Ravé, Bieke Janssen, Chritica Lodder, Pablo Botella Lucena, Sofie Kessels, Jana Hardy, Eline Vandeput, Yanyan Wang, Ilie-Cosmin Stancu, Andrei Segal, Markus Kleinewietfeld, Thomas Voets, Bert Brône, Suresh Poovathingal, Yeranddy A. Alpizar, Ilse Dewachter
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引用次数: 0

Abstract

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.

Abstract Image

APOE缺乏抑制淀粉样蛋白促进(A) tau病理(T)和神经变性(N),在临床前模型中阻止进行性ATN病理
在AD中,淀粉样蛋白病理(A)先于tau病理(T)和神经变性(N)的进行性发展,后者(T/N)过程与症状进展相关。最近的抗β淀粉样蛋白(Aβ)临床试验带来了希望,但表明需要多靶向治疗,以有效阻止临床AD和ATN的病理进展。apoe相关的推定保护性突变(包括APOE3Christchurch, RELN-COLBOS)最近在对常染色体显性阿尔茨海默病异常高恢复力的病例报告中被发现。在这些病例中,Nature提供了阻止人类常染色体显性AD和ATN进展的概念证明,尽管淀粉样蛋白含量很高,并指出APOE途径是潜在的靶标。最近鉴定出APOE4纯合性为遗传性AD进一步支持了这一点。在这里,我们研究了APOE在临床前模型中的作用,该模型强有力地模拟了淀粉样蛋白促进(a) tau病理(T)和随后的神经变性(N),称为ATN模型,由5xFAD (F +)和TauP301S (T +)小鼠杂交产生。我们发现,APOE缺乏显著抑制了ATN模型中tau病理和tau诱导的神经变性的进展,尽管高a β负荷,让人想起高弹性ADAD病例报告。进一步的研究发现,尽管APOE缺乏的ATN小鼠的a β负荷(W02染色)增加,但ThioS染色的致密核心斑块显著减少。此外,在这个ATN临床前模型中,单细胞RNA测序(scRNA-seq)显示APOE在小胶质细胞从稳态小胶质细胞转化为反应性和疾病相关小胶质细胞(DAM)的过程中起着至关重要的作用。在APOE存在的情况下,小胶质细胞消除显著降低了淀粉样蛋白驱动的tau病理,但在APOE缺乏的小鼠中没有。这些数据表明,APOE缺乏抑制淀粉样蛋白驱动的tau病理和随后的神经退行性变,其多效性包括防止致密的核心斑块形成和停止稳态小胶质细胞的转化。我们在此提出了一个模型,概述了APOE缺乏对淀粉样蛋白促进的tau病理的抑制,尽管a β载量很高,这对于理解APOE和APOE依赖过程在ATN进展及其在AD中的治疗利用中的作用很重要。
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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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