Xie M, Miller A, Pallegar P, Umpierre A, Liang Y, Wang N, Zhang S, Nagaraj N, Zachary F, Qi F, Ghayal N, Oskarsson B, Zhao S, Zheng J, Nguyen A, Dickson DW, Wu L-J. Rod-shaped microglia interact with neuronal dendrites to regulate cortical excitability in TDP-43 related neurodegeneration. 2024 Jul 02 10.1101/2024.06.30.601396 (version 1) bioRxiv.
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University of Kentucky, Lexington
Rod-shaped microglia fascinated the founders of neuropathology, with pioneers like Nissl, Alzheimer, Cerletti, and Achúcarro describing these cells as Stäbchenzellen. Río-Hortega even dedicated a significant portion of his seminal work on microglia as the “third element” of the brain to analyzing these unique cells (Sierra et al., 2016). Despite early interest, much of what was known about these cells remained descriptive, especially in the context of disease and injury (Giordano et al., 2021).
Now, Long-Jun Wu’s lab has made another major discovery in microglia biology, demonstrating that microglia wrapping around neuronal processes, particularly apical dendrites, represents a neuroprotective response aimed at limiting neuronal hyperexcitability. This was in a mouse model of TDP-43 neurodegeneration (rNLS8). Using in vivo calcium imaging, spatial transcriptomics, and single-cell transcriptomics, Xie et al. found that rod-shaped microglia are spatially and temporally associated with neuronal hyperexcitability.
They identified TREM2 as a key regulator in the formation of these microglia. When TREM2 was knocked out, there was a significant reduction in rod-shaped microglia, increased neuronal hyperexcitability, more severe motor deficits, and a shorter lifespan in the mice. These findings suggest that rod-shaped microglia are potentially neuroprotective. However, TREM2 knockout also reduced overall microglia density and size, affecting other microglial phenotypes as well.
This study adds to the growing body of evidence for the protective effects of reactive microglia. Rod-shaped microglia are observed in aging and Alzheimer’s disease (Bachstetter et al., 2017), potentially indicating a response to reduce neuronal hyperexcitability. Interestingly, not all individuals with Alzheimer’s disease have rod-shaped microglia (Bachstetter et al., 2017), raising critical questions about their role. Are some individuals with Alzheimer’s experiencing hyperexcitable neurons to which microglia fail to respond, worsening brain health? Evidence of rod-shaped microglia in people who age without advanced neurodegenerative pathology supports their protective role. Alternatively, do rod-shaped microglia identify individuals with abnormally high levels of neuronal hyperexcitability?
Xie et al. identified additional molecular targets, such as Galectin-3, that could be used alongside or as alternatives to TREM2 to manipulate rod-shaped microglia. Utilizing new, more specific tools to study these cells could significantly advance our understanding of how microglia promote healthy aging and combat disease. These advancements may lead to novel therapeutic strategies that enhance microglial protective functions, improving outcomes for those with neurodegenerative diseases.
Given Long-Jun Wu’s lab expertise in in vivo imaging of microglia, I am incredibly excited to see where this project goes next. It would be fascinating to observe how rod-shaped microglia interact with hyperexcitable neurons in real-time. Manipulating the microglia in real-time and observing the changes in neuronal activity would be a dream experiment. This could provide unprecedented insights into the dynamic role of microglia in regulating neuronal function, and potentially lead to new therapeutic strategies for neurodegenerative diseases.
References:
Sierra A, de Castro F, Del Río-Hortega J, Rafael Iglesias-Rozas J, Garrosa M, Kettenmann H. The "Big-Bang" for modern glial biology: Translation and comments on Pío del Río-Hortega 1919 series of papers on microglia. Glia. 2016 Nov;64(11):1801-40. PubMed.
Giordano KR, Denman CR, Dubisch PS, Akhter M, Lifshitz J. An update on the rod microglia variant in experimental and clinical brain injury and disease. Brain Commun. 2021;3(1):fcaa227. Epub 2021 Jan 4 PubMed.
Bachstetter AD, Ighodaro ET, Hassoun Y, Aldeiri D, Neltner JH, Patel E, Abner EL, Nelson PT. Rod-shaped microglia morphology is associated with aging in 2 human autopsy series. Neurobiol Aging. 2017 Apr;52:98-105. Epub 2017 Jan 5 PubMed.
View all comments by Adam BachstetterBrigham and Women's Hospital, Boston
This study entangles an interesting observation related to the detection of “rod-shaped” microglia in ALS pathology. RNA-Seq analysis identified a cluster of disease-associated microglia (DAM) enriched in Lgals3 (Galectin-3) expression in a mouse model of ALS. We, and others, have shown that Lgals3+ microglia play a beneficial role in microglial response to neurodegeneration (MGnD/ aka DAM) (Yin et al., 2023; Yu et al., 2024). Thus, the discovery that TREM2 deletion exacerbates disease progression via the elimination of Lgals3+ “rod-shaped microglia” relevant to the field.
However, it is still unknown whether the Lgals3+ rod-shaped microglia, detected using immunohistochemistry in this study, truly represent microglia or if they are infiltrating macrophages. Moreover, since global TREM2-KO mice were used in this study, it is possible that the observed effect is due to deletion of TREM2 in peripheral myeloid cells. Future studies will be required to dissect the contribution of microglia and peripheral myeloid cells expressing TREM2 to ALS progression.
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Yu C, Lad EM, Mathew R, Shiraki N, Littleton S, Chen Y, Hou J, Schlepckow K, Degan S, Chew L, Amason J, Kalnitsky J, Bowes Rickman C, Proia AD, Colonna M, Haass C, Saban DR. Microglia at sites of atrophy restrict the progression of retinal degeneration via galectin-3 and Trem2. J Exp Med. 2024 Mar 4;221(3) Epub 2024 Jan 30 PubMed.
View all comments by Neta RosenzweigMake a Comment
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