Abstract
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.
Highlights
Brains of Alzheimer’s disease (AD) patients are diagnostically characterized by amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), which develop in a characteristic spatiotemporal way [24, 47]
Tau‐seeding in 5xFAD/PS19 mice results in a bilateral propagation of tau pathology associated with neuronal atrophy, recapitulating the ATN pathological features of human AD Previous seminal work has shown that injection of human AD-tau in mice that harbor amyloid plaques results in the propagation of endogenous tau aggregates that surround Aβ plaques (NP tau) or develop into neurofibrillary tangles (NFTs) [21, 66]
This represents a compelling model for amyloid-facilitated progressive tau pathology as observed in AD patients, and emphasizes the importance of this early process in AD
Summary
Brains of AD patients are diagnostically characterized by amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), which develop in a characteristic spatiotemporal way [24, 47]. To. Lodder et al acta neuropathol commun (2021) 9:108 develop a biological definition of AD, biomarkers are used as proxies for the respective pathological changes in the brain, as framed in the ATN classification (NIAAA framework) [27, 28]. Lodder et al acta neuropathol commun (2021) 9:108 develop a biological definition of AD, biomarkers are used as proxies for the respective pathological changes in the brain, as framed in the ATN classification (NIAAA framework) [27, 28] Within this framework, different pathological stages of AD are presented, which range from an amyloid-stage to those that include progressive tau pathology and neurodegeneration. A better understanding of these synergisms and its modulation by neuroinflammation requires detailed analysis in humans, and in preclinical models that recapitulate progressive combined ATN pathology, compared to models with A and T pathology only
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
