sTREM-1 promotes the phagocytic function of microglia to induce hippocampus damage via the PI3K–AKT signaling pathway

Lü, Li; Li, Xuan; Fu, Juanhua; Liang, Jun; Hou, Yayi; Dou, Huan

doi:10.1038/s41598-022-10973-8

Cited by 14 publications

(7 citation statements)

References 113 publications

(105 reference statements)

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“…Triggering receptor expressed on myeloid cells 1 (TREM1) is a transmembrane receptor that can amplify inflammation through activation of the spleen tyrosine kinase (SYK) [ 47 ]. Soluble TREM1 (sTREM1) is released in response to inflammation and can contribute to hippocampal neuronal damage and synaptic loss via the PI3K–AKT signaling pathway [ 48 ]. NF-κB signaling can be upregulated by activation of PI3K–AKT signaling [ 49 ], suggesting that female-biased TREM1 activity may be upstream of the female-biased NF-κB upregulation in old microglia.…”

Section: Resultsmentioning

confidence: 99%

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

Ocañas¹,

Pham²,

Cox³

et al. 2023

J Neuroinflammation

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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 associated with late-onset AD. Here, we examined and compared transcriptomic and translatomic sex effects in young and old murine hippocampal microglia. 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 for RNA-sequencing and differential expression analyses. Flow cytometry, qPCR, and imaging approaches were used to confirm the transcriptomic and translatomic 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 emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Normalized gene expression values can be accessed through a searchable web interface (https://neuroepigenomics.omrf.org/). Pathway analyses 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 determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.

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Section: Resultsmentioning

confidence: 99%

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

Ocañas¹,

Pham²,

Cox³

et al. 2023

J Neuroinflammation

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“…Of potential relevance to age-related loss of motor synapses, the translatomes of both aged female and male motor neurons are enriched for genes with roles in the complement system and TREM1 signaling ( Figure 8H ). Both complement signaling ( 62 – 66 ) and TREM1 ( 67 , 68 ) have been shown to mediate synaptic pruning by microglia; thus, motor neurons undergo molecular changes during aging that may cause microglia to target motor synapses.…”

Section: Resultsmentioning

confidence: 99%

Aging alters mechanisms underlying voluntary movements in spinal motor neurons of mice, primates, and humans

Castro¹,

Lopes²,

Settlage³

et al. 2023

JCI Insight

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Spinal motor neurons have been implicated in the loss of motor function that occurs with advancing age. However, the cellular and molecular mechanisms that impair the function of these neurons during aging remain unknown. Here, we show that motor neurons do not die in old female and male mice, rhesus monkeys, and humans. Instead, these neurons selectively and progressively shed excitatory synaptic inputs throughout the soma and dendritic arbor during aging. Thus, aged motor neurons contain a motor circuitry with a reduced ratio of excitatory to inhibitory synapses that may be responsible for the diminished ability to activate motor neurons to commence movements. An examination of the motor neuron translatome (ribosomal transcripts) in male and female mice reveals genes and molecular pathways with roles in glia-mediated synaptic pruning, inflammation, axonal regeneration, and oxidative stress that are upregulated in aged motor neurons. Some of these genes and pathways are also found altered in motor neurons affected with amyotrophic lateral sclerosis (ALS) and responding to axotomy, demonstrating that aged motor neurons are under significant stress. Our findings show mechanisms altered in aged motor neurons that could serve as therapeutic targets to preserve motor function during aging.

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“…Triggering receptor expressed on myeloid cells 1 (TREM1) is a transmembrane receptor that can amplify inflammation through activation of the spleen tyrosine kinase (SYK) (37). Soluble TREM1 (sTREM1) is released in response to inflammation and can contribute to hippocampal neuronal damage and synaptic loss via the PI3K-AKT signaling pathway (38). NF-κB signaling can be upregulated by activation of PI3K-AKT signaling (39), suggesting that female-biased TREM1 activity may be upstream of the female-biased NF-κB upregulation in old microglia.…”

Section: Resultsmentioning

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.

show abstract

sTREM-1 promotes the phagocytic function of microglia to induce hippocampus damage via the PI3K–AKT signaling pathway

Cited by 14 publications

References 113 publications

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

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

Aging alters mechanisms underlying voluntary movements in spinal motor neurons of mice, primates, and humans

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

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