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Integrated Stress Response Associated with Dark Microglia Contributes to Neurodegeneration

44 Pages Posted: 18 Apr 2024 Publication Status: Accepted

See all articles by Anna Flury

Anna Flury

CUNY - The Graduate Center

Leen Aljayousi

CUNY - The Graduate Center

Siaresh Aziz

CUNY - The Graduate Center

Hye-Jin Park

CUNY - The Graduate Center

Mohammadparsa Khakpour

University of Victoria

Colby Sandberg

University of Victoria

Fernando González Ibáñez

University of Victoria

Olivia Braniff

University of Victoria

Pragney Deme

Johns Hopkins University

Jackson D. McGrath

University of Michigan at Ann Arbor

Thi Ngo

CUNY - The Graduate Center

Jack Mechler

CUNY - The Graduate Center

Denice Moran Ramirez

CUNY - The Graduate Center

Dvir Avnon-Klein

CUNY - The Graduate Center

John W. Murray

Columbia University

Jia Liu

CUNY - The Graduate Center

Norman J. Haughey

Johns Hopkins University

Sebastian Werneburg

University of Michigan at Ann Arbor

Marie-Eve Tremblay

University of Victoria; Université Laval - Centre de Recherche du CHU de Québec-Université Laval

Pinar Ayata

CUNY - The Graduate Center

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Abstract

Microglia, the brain’s primary resident immune cells, can assume various phenotypes with diverse functional outcomes on brain homeostasis. In Alzheimer’s disease (AD), where microglia are a leading causal cell type, the identity of microglia subsets that drive neurodegeneration remains unresolved. Here, we identify a microglia phenotype characterized by a conserved stress signaling pathway, the integrated stress response (ISR). Using mouse models to activate or inhibit ISR in microglia, we show that ISR underlies the ultrastructurally distinct “dark” microglia subset linked to pathological synapse loss. Inducing microglial ISR in murine AD models exacerbates neurodegenerative pathologies, such as Tau pathology and synaptic terminal loss. Conversely, inhibiting microglial ISR in AD models ameliorates these pathologies. Mechanistically, we present evidence that ISR promotes the secretion of toxic long- chain lipids that impair neuron and oligodendrocyte homeostasis in vitro. Accordingly, inhibition of lipid synthesis in AD models ameliorates synaptic terminal loss. Our results demonstrate that activation of ISR within microglia represents a pathway contributing to neurodegeneration and suggest that this may be sustained, at least in part, by the secretion of long-chain lipids from ISR-activated microglia.

Note:

Funding Information: This work was supported by the CUNY Research Foundation, Alzheimer’s Association AARG- 22-974642 (P.A.), Alfred P. Sloan Foundation JFRASE (P.A.), Provost’s Pre-Dissertation Science Research Fellowships (A.F., L.A.), CIHR Foundation FDN341846 (M.-E.T.), Tier II CRC in Neurobiology of Aging and Cognition CRC-2019-00407 (M.-E.T.), CFI John R. Evans Leaders Fund 39965 (M.-E.T.), National Multiple Sclerosis Society Grant TA-1905-34048 (S.W.), NIH R01 MH131219 (N.J.H), as well as generous support by Robin Chemers Neustein.

Conflict of Interests: The authors declare no competing interests.

Ethical Approval: The brain bank at CERVO Brain Research Center (QC, Canada) and handling of the post-mortem human tissues were approved by the Ethics Committee of the University of Victoria, Institut Universitaire en Santé Mentale de Québec, and Université Laval. Written consent was obtained for using post-mortem tissues, and all analyses were performed per the Code of Ethics of the World Medical Association. All animal protocols were approved by IACUC at CUNY Advanced Science Research Center CMU and performed according to NIH guidelines.

Keywords: microglia, neurodegeneration, integrated stress response, ISR, dark microglia, Alzheimer's Disease, non-cell-autonomous signaling

Suggested Citation

Flury, Anna and Aljayousi, Leen and Aziz, Siaresh and Park, Hye-Jin and Khakpour, Mohammadparsa and Sandberg, Colby and Ibáñez, Fernando González and Braniff, Olivia and Deme, Pragney and McGrath, Jackson D. and Ngo, Thi and Mechler, Jack and Ramirez, Denice Moran and Avnon-Klein, Dvir and Murray, John W. and Liu, Jia and Haughey, Norman J. and Werneburg, Sebastian and Tremblay, Marie-Eve and Ayata, Pinar, Integrated Stress Response Associated with Dark Microglia Contributes to Neurodegeneration. Available at SSRN: https://ssrn.com/abstract=4795157 or http://dx.doi.org/10.2139/ssrn.4795157
This version of the paper has not been formally peer reviewed.

Anna Flury

CUNY - The Graduate Center ( email )

Leen Aljayousi

CUNY - The Graduate Center ( email )

Siaresh Aziz

CUNY - The Graduate Center ( email )

Hye-Jin Park

CUNY - The Graduate Center ( email )

Mohammadparsa Khakpour

University of Victoria ( email )

3800 Finnerty Rd
Victoria, V8P 5C2
Canada

Colby Sandberg

University of Victoria ( email )

3800 Finnerty Rd
Victoria, V8P 5C2
Canada

Fernando González Ibáñez

University of Victoria ( email )

3800 Finnerty Rd
Victoria, V8P 5C2
Canada

Olivia Braniff

University of Victoria ( email )

3800 Finnerty Rd
Victoria, V8P 5C2
Canada

Pragney Deme

Johns Hopkins University ( email )

Baltimore, MD 20036-1984
United States

Jackson D. McGrath

University of Michigan at Ann Arbor ( email )

Ann Arbor, MI
United States

Thi Ngo

CUNY - The Graduate Center ( email )

Jack Mechler

CUNY - The Graduate Center ( email )

Denice Moran Ramirez

CUNY - The Graduate Center ( email )

Dvir Avnon-Klein

CUNY - The Graduate Center ( email )

John W. Murray

Columbia University ( email )

3022 Broadway
New York, NY 10027
United States

Jia Liu

CUNY - The Graduate Center ( email )

Norman J. Haughey

Johns Hopkins University ( email )

Baltimore, MD 20036-1984
United States

Sebastian Werneburg

University of Michigan at Ann Arbor ( email )

Ann Arbor, MI
United States

Marie-Eve Tremblay

University of Victoria

3800 Finnerty Rd
Victoria, V8P 5C2
Canada

Université Laval - Centre de Recherche du CHU de Québec-Université Laval ( email )

Québec
Canada

Pinar Ayata (Contact Author)

CUNY - The Graduate Center ( email )

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