Perivascular cells induce microglial phagocytic states and
            synaptic engulfment via SPP1 in mouse models of Alzheimer’s
            disease

Schepper, Sebastiaan De; Ge, Judy Z; Crowley, Gerard; Ferreira, Laís S. S.; Garceau, Dylan; Toomey, Christina E.; Sokolova, Dimitra; Rueda-Carrasco, Javier; Shin, Sunhye; Kim, Jung Seok; Childs, Thomas E.; Lashley, Tammaryn; Burden, Jemima J.; Sasner, Michael; Frigerio, Carlo Sala; Hong, Soyon

doi:10.1038/s41593-023-01257-z

Cited by 99 publications

(88 citation statements)

References 87 publications

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“…Complement-dependent engulfment has frequently been implicated in excessive synaptic elimination leading to functional deficits 37, 38, 40 . In the CNS, α-syn is known to be enriched at presynapses 48 , but the subcellular localization of α-syn within enteric neurons is unknown.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, we found that enteric α-syn preferentially localizes to the pre-synaptic space. Moreover, although excessive synaptic pruning due to α-syn has not been shown, it is a well-studied mechanism for cognitive dysfunction in Alzheimer’s-related pathology 37, 38, 70 . Additionally, ENS macrophages engage in synaptic refinement during development 23 .…”

Section: Discussionmentioning

confidence: 99%

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Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology

Mackie,

Koshy,

Bhogade

et al. 2023

Preprint

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SummaryDeposition of misfolded α-synuclein (αsyn) in the enteric nervous system (ENS) is found in multiple neurodegenerative diseases. It is hypothesized that ENS synucleinopathy contributes to both the pathogenesis and non-motor morbidity in Parkinson’s Disease (PD), but the cellular and molecular mechanisms that shape enteric histopathology and dysfunction are poorly understood. Here, we demonstrate that ENS-resident macrophages, which play a critical role in maintaining ENS homeostasis, initially respond to enteric neuronal αsyn pathology by upregulating machinery for complement-mediated engulfment. Pharmacologic depletion of ENS-macrophages or genetic deletion of C1q enhanced enteric neuropathology. Conversely, C1q deletion ameliorated gut dysfunction, indicating that complement partially mediates αsyn-induced gut dysfunction. Internalization of αsyn led to increased endo-lysosomal stress that resulted in macrophage exhaustion and temporally correlated with the progression of ENS pathology. These novel findings highlight the importance of enteric neuron-macrophage interactions in removing toxic protein aggregates that putatively shape the earliest stages of PD in the periphery.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology

Mackie,

Koshy,

Bhogade

et al. 2023

Preprint

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“…Of interest, Spp1 is increased in microglia from mouse models of AD (18, 50) and a marker of the DAM/ARM/MGnD phenotype. Recently, perivascular macrophage expression of Spp1 was shown to be necessary for microglial engulfment of synapses and upregulation of phagocytic markers in the mouse hippocampus with amyloid pathology (51). This finding suggests that higher expression of Spp1 in aged female microglia may lead to a greater susceptibility to neurodegeneration in AD.…”

Section: Discussionmentioning

confidence: 99%

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

Ocañas

Pham

Cox

et al. 2023

Preprint

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Background Microglia, the brain's principal immune cells, have been implicated in the pathogenesis of Alzheimer's disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment that is associated with late-onset AD. Here, we examined and compared the transcriptomic and translatomic sex effects in young and old mouse hippocampus. Methods Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome, respectively, for RNA-sequencing and differential expression analyses. Flow cytometry was used to confirm the transcriptomic findings. Results There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally- and autosomally-encoded sex differences emerge with aging. These sex DEGs identified at old age were primarily female-biased and were enriched in senescent and disease-associated microglial signatures. Pathway analysis identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP. Conclusions These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology, and explore how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.

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“…Despite the quantifiable neuropathology of β-amyloid plaques (Aβ) and neurofibrillary tangles (NFTs) 6 , the exact neurobiological mechanisms underlying Alzheimer's disease (AD) remain elusive. Brain myeloid-origin immune cells, including microglia and perivascular macrophages (PVMs), play crucial roles in the pathogenesis of AD [1][2][3][4][7][8][9][10] , providing neuroprotective benefits by clearing lesions, but also exacerbating the disease through the induction of excessive neuroinflammation 11 . While previous studies utilizing single-nucleus/-cell RNA sequencing (snRNA-seq/scRNA-seq) have made significant progress describing complex functional roles of murine and human microglia in AD 4,[12][13][14][15] , challenges with characterizing the wide spectrum of microglial heterogeneity and identifying more nuanced AD-associated subtypes still remain, largely due to limited sample sizes and differences in the single-cell technologies used.…”

Section: Mainmentioning

confidence: 99%

“…

Microglia and perivascular macrophages, myeloid-origin resident immune cells in the human brain, play crucial roles in Alzheimer's disease (AD) [1][2][3][4] . However, the field lacks a unified taxonomy describing their heterogeneity and plasticity 5 .

…”

mentioning

confidence: 99%

Plasticity of Human Microglia and Brain Perivascular Macrophages in Aging and Alzheimer’s Disease

Lee,

Porras,

Spencer

et al. 2023

Preprint

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Microglia and perivascular macrophages, myeloid-origin resident immune cells in the human brain, play crucial roles in Alzheimer's disease (AD)1-4. However, the field lacks a unified taxonomy describing their heterogeneity and plasticity5. To address this, we applied single-cell profiling to two independent, demographically diverse cohorts. The first comprises 543,012 viable myeloid cells from 137 unique postmortem brain specimens, while the second consists of 289,493 myeloid nuclei from 1,470 donors. Collectively, they cover the human lifespan and varying degrees of AD neuropathology. We identify 13 transcriptionally distinct myeloid subtypes, including the "GPNMB" subtype that proliferates with AD. We distinguish two contrasting homeostatic microglial states in AD and with aging: the first ("FRMD4A") wanes over time, while the second ("PICALM") becomes more prevalent. By prioritizing AD-risk genes, including PTPRG, DPYD, and IL15, and placing them into a regulatory hierarchy, we identify common upstream transcriptional regulators, namely MITF and KLF12, that regulate the expression of AD-risk genes in the opposite directions. Through the construction of cell-to-cell interaction networks, we identify candidate ligand-receptor pairs, including APOE:SORL1 and APOE:TREM2, associated with AD progression. We show polygenic risk for AD predisposes and prioritize the GPNMB subtype as a therapeutic target of early intervention. Our findings delineate the relationship between distinct functional states of myeloid cells and their pathophysiological response to aging and AD, providing a significant step toward the mechanistic understanding of the roles of microglia in AD and the identification of novel therapeutics.

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Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer’s disease

Cited by 99 publications

References 87 publications

Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology

Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

Plasticity of Human Microglia and Brain Perivascular Macrophages in Aging and Alzheimer’s Disease

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