. Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer's disease. Nat Neurosci. 2023 Jul;26(7):1196-1207. Epub 2023 Jun 8 PubMed.


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  1. This new manuscript from Yin and colleagues adds important information to our understanding of how miR-155 impacts microglia gene expression in the context of an AD model. It also confirms our previously reported findings that microglia-specific conditional knockout of miR-155 yields reduced amyloid plaque burden in APP/PS1 mice. These studies differ in that the impact of microglia-specific deletion of miR155 on seizures and mortality that we recently reported was not addressed here (Aloi et al., 2023). It is unclear if these negative effects of the same genetic manipulation were not observed, or just not reported.

    The APP/PS1 model is well known to exhibit seizures and seizure-related mortality, but background strain could influence the rates at which this phenotype is observed. The modest, but statistically significant improvement on a single behavioral assay reported in Yin et al., should be taken in context. The assay may have been performed in a subset of animals with heightened resilience to seizures or to the enhanced synaptic pruning by miR-155 deficient microglia that we observed.

    View all comments by Gwenn A. Garden
  2. I agree that the ablation of miR-155 in microglia promotes their transition into an IFN-γ responsive state in a mouse model of amyloidosis. I also agree that the data show that mIR-155 ablation in microglia leads to the cells being more adept at phagocytosis, and at containment of Aβ plaques. The effect of plaque load overall was small, but there was reduced peri-plaque neuritic dystrophy and less synaptic loss surrounding plaques. APP/PS1 mice without microglial mIR-155 performed better on memory tests, and lost fewer synapses. Notably, these improvements were decreased when mIR-155 was knocked out of microglia. They did not test whether IFN-γ blockade in APP/PS1 mice affected behavior.

    The findings are clear that miR-155 KO in microglia results in a more MgND/DAM state of gene expression and in the presence of amyloid, there is greater plaque compaction and decreased plaque associated dystrophic neurites and peri-plaque synaptic loss. It is likely that IFN-γ signaling causes similar effects as miR-155 KO of microglia in this mouse model. The work appears very well done and suggests a beneficial role of either knocking down miR-155 in microglia of stimulation of microglial IFN-γ signaling in the early phase of amyloid deposition.

    From the perspective of the translational implications of these findings, the APP/PS1 mice are a useful model of Aβ amyloidosis. The amyloid deposition that occurs in these, and similar models, develops no major neuronal and synaptic loss, and the major damage that occurs is immediately surrounding amyloid plaques. The brain changes in these mice mimic the ~20 year period called “preclinical” AD in humans, when amyloid is accumulating, cognition is normal, and there is no neurodegeneration (loss of neurons and brain volume). The kind of microglial response that occurs when miR-155 is knocked out (more MgND-like with increased IFN signature) in this “stage” of disease appears protective by resulting in more contained plaques and less associated plaque toxicity. A treatment that resulted in similar effects in humans would likely be useful during the “preclinical” phase of AD. However, when other changes begin to occur within the AD brain such as tau pathology, which is linked with cognitive decline and neurodegeneration, as well as a different inflammatory environment, the microglial state induced by miR-155 or IFN-γ may not have the same effects that are associated with neuroprotection as shown here. 

    Work in other model systems that develop neurodegeneration, such as occurs with tau pathology, may be helpful to sort out when to try to target these pathways during different stages of AD.

    View all comments by David Holtzman
  3. Disentangling the complexity of microRNA regulation in the brain is challenging. Deconvoluting the significance of microglial priming in physiology and disease is strenuous. Trying to concomitantly probe both is commendable.

    Yin et al. show that microglial deletion of miR-155 enhances induction of the MGnD microglial state, aka disease-associated microglia (DAM), via the IFN-γ pathway, which further attenuates amyloid, neuritic, and synaptic pathology, and improves cognition in AD mice. These observations provide the foundation for further exploring miR-155 as a therapeutic target in AD, as has already been proposed for other microRNAs (Walgrave et al., 2023). Our increasing understanding of both microRNA and AD mechanistic complexity puts microRNAs forward as promising multi-targeting approaches to therapy. However, this exact advantage is the same that—on the flip side—may jeopardize the safety of microRNA therapeutic applications: Do microRNAs also exert non-disease-relevant, putatively toxic effects in a given context (as it was recently shown for miR-155, Aloi et al., 2023), and could the many microRNA targets prove to be “too many” for clinical use (Walgrave et al., 2021)? 

    These questions, among others, are inevitably at the core of the study by Yin et al.

    Previous work by the Butovsky group has demonstrated a link between TREM2-APOE signaling, microglial transition to the MGnD state, and miR-155 (Krasemann et al., 2017). This microglial priming was associated (as opposed to the current findings) with the loss of protective MGnD function and the active induction of neurodegenerative phenotypes. Hence, the results of the recent Yin et al. study should be viewed through the prism of a bi- (or even multi-) modal, and disease-stage-specific effect of TREM2 on microglia pathophysiology. Interestingly, microglial deletion of miR-155 in wild-type mice resulted in the suppression of homeostatic microglial gene expression, further suggesting that the interplay between miR-155 and microglial priming is likely highly complex and would, therefore, require systematic assessment in a preclinical setting.

    The authors propose miR-155 depletion as a therapeutic strategy in AD. This is a valid approach given that increased miR-155 levels were observed in their APP/PS1 AD mouse model. Yet, this is not a consistent observation in the human AD brain (Sierksma et al., 2018; Lau et al., 2013). Further work with more and larger patient cohorts would be required to strengthen the translational relevance of the findings by Yin et al., especially given that systemic miR-155 deletion was previously shown to accelerate Aβ deposition in APP/PS1 mice (Readhead et al., 2018). 

    Another critical point, also raised by the authors, is the specificity of their genetic approach for microglial targeting. The Cx3cr1-Cre mouse line does not express Cre solely in microglia, but also in other macrophages, even if that remained below the detection or resolution threshold of the present study. Also relevant to this point, the specificity of miR-155 expression for microglia is not entirely clear in the literature: miR-155 has been previously also identified in neurons in the human brain (Sierksma et al., 2018), while prior work by corresponding author Oleg Butovsky, Howard Weiner and colleagues (Butovsky et al., 2014) showed that miR-155 is expressed at similar levels in adult mouse microglia, astrocytes, oligodendrocytes and primary embryonic cortical neuronal cultures. Hence, in terms of therapeutic relevance, it may also be valuable to address non-microglial (cell autonomous or non-cell autonomous) effects of miR-155 in the brain.

    Even though several questions remain unanswered, one should view all the challenges showcased in the work of Yin et al. as the way to move forward in our research on critically assessing the therapeutic potential of microRNAs in AD: microRNA biology is complex and context-dependent, directly and indirectly affecting a broad range of large molecular target networks (going beyond single, direct-target molecules operating in only one cellular population) in often intricate feed-forward and feedback regulatory loops. Microglial activation and its role in AD pathology and progression are similarly convoluted. Why then, should our approach to understanding the mechanisms and therapeutic targeting of miRNAs in AD be a simple one?


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    View all comments by Evgenia Salta

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  1. Ridding Microglia of a MicroRNA Compacts Amyloid, Protects Synapses