CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia

Acta Neuropathologica Communications

Ilse Dewachter¹  Manuel Gutiérrez de Ravé¹  Tim Vanmierlo¹  Pablo Botella Lucena¹  Bert Brône¹  Chritica Lodder¹  Hannah Vanrusselt¹  Niels Cremers¹  Ilie Cosmin Stancu¹  Sarah Vanherle¹  Jean-Noël Octave²  Bernard Hanseeuw³  Isabelle Scheyltjens⁴  Kiavash Movahedi⁴  Astrid Bottelbergs⁵ 

[1] Department of Neurosciences, Biomedical Research Institute, Hasselt University, Hasselt, Belgium;Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium;Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium;Department of Neurology, Cliniques Universitaires Saint-Luc, Brussels, Belgium;Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA;Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium;Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium;Laboratory for Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Beerse, Belgium;Neuroscience Department, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium;

关键词: Alzheimer’s disease;    Amyloid pathology;    Tau pathology;    Neurodegeneration;    ATN-continuum;    Microgliosis;    Microglial profiling;    CSF1R inhibition;   

DOI  :  10.1186/s40478-021-01204-8

来源: Springer

【 摘 要 】

Alzheimer's disease (AD) is characterized by a sequential progression of amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), constituting ATN pathology. While microglia are considered key contributors to AD pathogenesis, their contribution in the combined presence of ATN pathologies remains incompletely understood. As sensors of the brain microenvironment, microglial phenotypes and contributions are importantly defined by the pathologies in the brain, indicating the need for their analysis in preclinical models that recapitulate combined ATN pathologies, besides their role in A and T models only. Here, we report a new tau-seed model in which amyloid pathology facilitates bilateral tau propagation associated with brain atrophy, thereby recapitulating robust ATN pathology. Single-cell RNA sequencing revealed that ATN pathology exacerbated microglial activation towards disease-associated microglia states, with a significant upregulation of Apoe as compared to amyloid-only models (A). Importantly, Colony-Stimulating Factor 1 Receptor inhibition preferentially eliminated non-plaque-associated versus plaque associated microglia. The preferential depletion of non-plaque-associated microglia significantly attenuated tau pathology and neuronal atrophy, indicating their detrimental role during ATN progression. Together, our data reveal the intricacies of microglial activation and their contributions to pathology in a model that recapitulates the combined ATN pathologies of AD. Our data may provide a basis for microglia-targeting therapies selectively targeting detrimental microglial populations, while conserving protective populations.

【 授权许可】

CC BY