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

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.

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

“…Blockade of microglial proliferation by CSF1R inhibitor JNJ-40346527 (JNJ-527) attenuated tau-induced neurodegeneration in the P301S mouse tauopathy model ( Mancuso et al, 2019 ). Lodder et al (2021) revealed that pharmacological targeting of CSF1R preferentially eliminated non-plaque-associated microglia and rescued tau pathology and neurodegeneration in a combined AD pathologies mouse model, while preserving protective plaque associated microglia. Administration of PLX5622 dramatically reduced propagation of p-tau in App NL– G –F mouse, a humanized APP mutant knock-in homozygote mouse ( Clayton et al, 2021 ).…”

Should We Open Fire on Microglia? Depletion Models as Tools to Elucidate Microglial Role in Health and Alzheimer’s Disease

“…In addition, we observed a significant increment in the expression of the microglial activation marker Clec7a and a trend of increase in Trem2 and Cd45 markers after 7 days of repopulation ( Figure 1 E), which may allow the remaining microglia to be less dependent on CSF1R signaling. In this sense, Lodder et al (2021) have shown that active Aβ-associated microglia were more resistant to PLX3397 treatment [ 71 ]. Additionally, it has been described in vitro that TREM2 signaling induces the activation of Syk pathway (downstream to CSF1R), in such a way that it synergizes with the CSF1-CSF1R axis [ 72 ].…”

“…While plaque-associated microglia may be protective, non-plaque-associated microglia, also in the presence of Tau pathology, could display neurotoxic functions. In this sense, it has been recently demonstrated that the preferential depletion of microglia distal to amyloid deposits significantly attenuated Tau pathology and neuronal atrophy in Tau-seeding 5xFAD/PS19 mice [ 71 ]. In this model, while Aβ-associated DAM microglia may compact amyloid plaques and limit its toxicity, non-plaque-associated microglia may contribute to Tau spread and to a pro-inflammatory environment that could mediate neuronal dysfunction.…”

Towards PET imaging of the dynamic phenotypes of microglia

“…In transgenic AD mice, high CSF‐1R expression is found in close proximity to Aβ aggregates [ 116 , 117 ]. More recently, plaque‐associated microglia were found to be more resistant to microglia depletion by CSF‐1R inhibition than non‐plaque‐associated microglia in a mouse model displaying both Aβ and tau pathology [ 118 ]. In MS lesions, CSF‐1R expression was lower than in NAWM and in EAE mice, CSF‐1R inhibitors reduced disease severity [ 113 ].…”