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.
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.