SYK coordinates neuroprotective microglial responses in neurodegenerative disease

Ennerfelt, Hannah; Frost, Elizabeth; Shapiro, Daniel; Holliday, Coco; Zengeler, Kristine E.; Voithofer, Gabrielle; Bolte, Ashley C.; Lammert, Catherine R.; Kulas, Joshua A.; Ulland, Tyler K.; Lukens, John R.

doi:10.1016/j.cell.2022.09.030

Cited by 126 publications

(120 citation statements)

References 81 publications

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“…In‐line with these findings, an independent study published alongside our paper similarly showed that SYK signalling in microglia is required to support efficient containment and disposal of Aβ in the 5xFAD mouse model of AD 10 . Both of our groups also revealed that boosting SYK activation can offer a robust strategy to enhance Aβ control in mouse models of AD 9,10 . More specifically, our collective studies demonstrated that activating the SYK‐associated receptor CLEC7A via injection with either anti‐CLEC7A antibodies or a natural, fungal‐derived CLEC7A ligand both offer effective interventions to limit amyloidosis in 5xFAD mice.…”

Section: Figuresupporting

confidence: 77%

“… 10 Both of our groups also revealed that boosting SYK activation can offer a robust strategy to enhance Aβ control in mouse models of AD. 9 , 10 More specifically, our collective studies demonstrated that activating the SYK‐associated receptor CLEC7A via injection with either anti‐CLEC7A antibodies or a natural, fungal‐derived CLEC7A ligand both offer effective interventions to limit amyloidosis in 5xFAD mice.…”

Section: Figurementioning

confidence: 96%

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Microglia rely on SYK signalling to mount neuroprotective responses in models of Alzheimer's disease and multiple sclerosis

Ennerfelt

Lukens

2023

Clinical & Translational Med

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Section: Figuresupporting

confidence: 77%

Section: Figurementioning

confidence: 96%

Microglia rely on SYK signalling to mount neuroprotective responses in models of Alzheimer's disease and multiple sclerosis

Ennerfelt

Lukens

2023

Clinical & Translational Med

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“…There was no such change in the expression of these genes in macrophage cluster 5. Instead, several genes were upregulated in the morphine group, including C-type lectin domain family 7 member A (CLEC7A), a myeloid-predominant pattern-recognition receptor implicated in protection from Alzheimer’s disease ( 99 , 100 ), type II major histocompatibility genes such as MAMU-DQA1, which are increased in macrophage activation ( 101 ), and the intermediate filament protein gene vimentin (VIM), which is increased in macrophages differentiation and activation ( 102 ). None of these genes had appreciable expression in the microglial clusters.…”

Section: Resultsmentioning

confidence: 99%

Morphine suppresses peripheral responses and transforms brain myeloid gene expression to favor neuropathogenesis in SIV infection

et al. 2022

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The twin pandemics of opioid abuse and HIV infection can have devastating effects on physiological systems, including on the brain. Our previous work found that morphine increased the viral reservoir in the brains of treated SIV-infected macaques. In this study, we investigated the interaction of morphine and SIV to identify novel host-specific targets using a multimodal approach. We probed systemic parameters and performed single-cell examination of the targets for infection in the brain, microglia and macrophages. Morphine treatment created an immunosuppressive environment, blunting initial responses to infection, which persisted during antiretroviral treatment. Antiretroviral drug concentrations and penetration into the cerebrospinal fluid and brain were unchanged by morphine treatment. Interestingly, the transcriptional signature of both microglia and brain macrophages was transformed to one of a neurodegenerative phenotype. Notably, the expression of osteopontin, a pleiotropic cytokine, was significantly elevated in microglia. This was especially notable in the white matter, which is also dually affected by HIV and opioids. Increased osteopontin expression was linked to numerous HIV neuropathogenic mechanisms, including those that can maintain a viral reservoir. The opioid morphine is detrimental to SIV/HIV infection, especially in the brain.

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“…Perhaps mouse models that are aged and genetically manipulated to progressively develop Aβ plaques and tau tangles may provide better models for testing TREM2 therapeutics. Additional microglial activating receptors have also been pointed out by genetic and experimental studies as new drug candidates, such as TAM receptors and CLEC7A [158,211,212]. The development of all these approaches will help to design effective and individually tailored therapeutics for AD.…”

Section: Discussionmentioning

confidence: 99%

TREM2 dependent and independent functions of microglia in Alzheimer’s disease

Hou

Chen

Grajales‐Reyes

et al. 2022

Mol Neurodegeneration

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Microglia are central players in brain innate immunity and have been the subject of extensive research in Alzheimer’s disease (AD). In this review, we aim to summarize the genetic and functional discoveries that have advanced our understanding of microglia reactivity to AD pathology. Given the heightened AD risk posed by rare variants of the microglial triggering receptor expressed on myeloid cells 2 (TREM2), we will focus on the studies addressing the impact of this receptor on microglia responses to amyloid plaques, tauopathy and demyelination pathologies in mouse and human. Finally, we will discuss the implications of recent discoveries on microglia and TREM2 biology on potential therapeutic strategies for AD.

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SYK coordinates neuroprotective microglial responses in neurodegenerative disease

Cited by 126 publications

References 81 publications

Microglia rely on SYK signalling to mount neuroprotective responses in models of Alzheimer's disease and multiple sclerosis

Microglia rely on SYK signalling to mount neuroprotective responses in models of Alzheimer's disease and multiple sclerosis

Morphine suppresses peripheral responses and transforms brain myeloid gene expression to favor neuropathogenesis in SIV infection

TREM2 dependent and independent functions of microglia in Alzheimer’s disease

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