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Myelin debris as an initiator of microglial dysfunction and neuropathology in Alzheimer’s disease

Cellular & Molecular Immunology volume 22, pages 208–210 (2025)Cite this article

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The Original Article was published on 01 January 2025

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Microglia, the resident immune cells of the brain, have emerged as key players in Alzheimer’s disease (AD) pathogenesis. On the one hand, microglia play beneficial roles in protecting the brain from pathological amyloid beta (Aβ) and neurofibrillary tau tangles (NFTs) in AD. Microglial responses can, however, become dysfunctional over time, which can lead to aberrant proinflammatory cytokine production and subsequent neuropathology [1, 2]. It is commonly thought that Aβ and NFTs serve as the major signals triggering microglial inflammation [1]. Therefore, it is logical to conceive that microglial neuroinflammation begins at the emergence of these pathological hallmarks. Interestingly, emerging evidence indicates that the onset of microglial inflammation often precedes Aβ and tau pathology [1], suggesting that additional signals in the AD brain may trigger microglial inflammation and kick-start AD progression.

To identify the specific components of myelin debris that are capable of inducing microglial inflammation in AD, Zhou et al. first isolated myelin debris from the brains of 5xFAD mice, a mouse model of AD-associated amyloidosis, and human AD patients and subjected the lipids to liquid chromatography‒mass spectrometry. Interestingly, the authors observed an enrichment in the abundance of LysoPS [5], a lipid class that has recently been found to incite inflammation in various neurological diseases, including multiple sclerosis and stroke [6]. However, whether LysoPS is also capable of triggering neuroinflammation and downstream neuropathology in AD has not been studied in great detail to date. Therefore, Zhou et al. generated an AD mouse model in which oligodendrocytes were unable to synthesize LysoPS enzymatically from phosphatidylserine and reported that reducing LysoPS production led to dampened plaque and tau pathology and reversed AD-associated memory impairments [5].

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Funding

We apologize to the authors whose work could not be referenced in this review owing to space limitations. Graphical illustrations were made via BioRender (https://biorender.com/). This work was supported by the National Institutes of Health/National Institute of Aging (R01AG071996, R01AG087406, and 1RF1AG078684; awarded to JRL), the Alzheimer’s Association (ADSF-21-816651; awarded to JRL), the Cure Alzheimer’s Fund (awarded to JRL), and the Owens Family Foundation (awarded to JRL). JDS was supported by a University of Virginia Brain Institute Presidential Fellowship and an Immunology Training Program Grant (5T32AI7496-28).

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Authors and Affiliations

  1. Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia (UVA), Charlottesville, VA, 22908, USA

    Joshua D. Samuels & John R. Lukens

  2. Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, 22908, USA

    Joshua D. Samuels & John R. Lukens

  3. Immunology Training Program, University of Virginia, Charlottesville, VA, 22908, USA

    Joshua D. Samuels & John R. Lukens

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  1. Joshua D. Samuels
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Correspondence to Joshua D. Samuels or John R. Lukens.

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Samuels, J.D., Lukens, J.R. Myelin debris as an initiator of microglial dysfunction and neuropathology in Alzheimer’s disease. Cell Mol Immunol 22, 208–210 (2025). https://doi.org/10.1038/s41423-024-01243-w

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