A neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion

Anna Flury; Leen Aljayousi; Hye-Jin Park; Mohammadparsa Khakpour; Jack Mechler; Siaresh Aziz; Jackson D McGrath; Pragney Deme; Colby Sandberg; Fernando González Ibáñez; Olivia Braniff; Thi Ngo; Simira Smith; Matthew Velez; Denice Moran Ramirez; Dvir Avnon-Klein; John W Murray; Jia Liu; Martin Parent; Susana Mingote; Norman J Haughey; Sebastian Werneburg; Marie-Ève Tremblay; Pinar Ayata

doi:10.1016/j.neuron.2024.11.018

A neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion

Neuron. 2024 Dec 19:S0896-6273(24)00875-4. doi: 10.1016/j.neuron.2024.11.018. Online ahead of print.

Authors

Anna Flury¹, Leen Aljayousi¹, Hye-Jin Park², Mohammadparsa Khakpour³, Jack Mechler⁴, Siaresh Aziz¹, Jackson D McGrath⁵, Pragney Deme⁶, Colby Sandberg³, Fernando González Ibáñez³, Olivia Braniff³, Thi Ngo², Simira Smith², Matthew Velez², Denice Moran Ramirez¹, Dvir Avnon-Klein², John W Murray⁷, Jia Liu², Martin Parent⁸, Susana Mingote¹, Norman J Haughey⁹, Sebastian Werneburg¹⁰, Marie-Ève Tremblay¹¹, Pinar Ayata¹²

Affiliations

¹ Neuroscience Initiative, Advanced Science Research Center, The City University of New York (CUNY) Graduate Center, New York, NY 10031, USA; Graduate Program in Biology, CUNY Graduate Center, New York, NY 10016, USA.
² Neuroscience Initiative, Advanced Science Research Center, The City University of New York (CUNY) Graduate Center, New York, NY 10031, USA.
³ Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C4, Canada.
⁴ Neuroscience Initiative, Advanced Science Research Center, The City University of New York (CUNY) Graduate Center, New York, NY 10031, USA; Graduate Program in Biochemistry, CUNY Graduate Center, New York, NY 10016, USA.
⁵ Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Michigan Medicine, Ann Arbor, MI 48105, USA.
⁶ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁷ Columbia Center for Human Development, Center for Stem Cell Therapies, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
⁸ CERVO Brain Research Center, Québec City, QC G1E 1T2, Canada.
⁹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Michigan Medicine, Ann Arbor, MI 48105, USA; Michigan Neuroscience Institute, Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
¹¹ Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C4, Canada; Department of Molecular Medicine, Université Laval, Québec City, QC G1V 0A6, Canada; Neurology and Neurosurgery Department, McGill University, Montréal, QC H3A 2B4, Canada; Canada Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 2A1, Canada; Centre for Advanced Materials and Related Technology and Institute on Aging and Lifelong Health, University of Victoria, Victoria, BC V8N 5M8, Canada.
¹² Neuroscience Initiative, Advanced Science Research Center, The City University of New York (CUNY) Graduate Center, New York, NY 10031, USA; Graduate Program in Biology, CUNY Graduate Center, New York, NY 10016, USA; Graduate Program in Biochemistry, CUNY Graduate Center, New York, NY 10016, USA. Electronic address: [email protected].

PMID: 39719704
DOI: 10.1016/j.neuron.2024.11.018

Abstract

The brain's primary immune cells, microglia, are a leading causal cell type in Alzheimer's disease (AD). Yet, the mechanisms by which microglia can drive neurodegeneration remain unresolved. Here, we discover that a conserved stress signaling pathway, the integrated stress response (ISR), characterizes a microglia subset with neurodegenerative outcomes. Autonomous activation of ISR in microglia is sufficient to induce early features of the ultrastructurally distinct "dark microglia" linked to pathological synapse loss. In AD models, microglial ISR activation exacerbates neurodegenerative pathologies and synapse loss while its inhibition ameliorates them. Mechanistically, we present evidence that ISR activation promotes the secretion of toxic lipids by microglia, impairing neuron homeostasis and survival in vitro. Accordingly, pharmacological inhibition of ISR or lipid synthesis mitigates synapse loss in AD models. Our results demonstrate that microglial ISR activation represents a neurodegenerative phenotype, which may be sustained, at least in part, by the secretion of toxic lipids.

Keywords: Alzheimer’s disease; ISR; dark microglia; integrated stress response; lipid secretion; lipotoxicity; microglia; neurodegeneration; neurotoxic microglia; non-cell-autonomous stress.