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CARD9 attenuates Ab pathology and modifies microglial responses in an Alzheimer’s disease mouse model

ABSTRACT: CARD9 attenuates Ab pathology and modifies microglial responses in an Alzheimer’s disease mouse model

PROVIDER: PRJNA973070 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24594700_1.fastq.gz	Fastqsanger.gz
	SRR24594700_2.fastq.gz	Fastqsanger.gz
	SRR24594701_1.fastq.gz	Fastqsanger.gz
	SRR24594701_2.fastq.gz	Fastqsanger.gz
	SRR24594702_1.fastq.gz	Fastqsanger.gz

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CARD9 attenuates Ab pathology and modifies microglial responses in an Alzheimer’s disease mouse model

Project description:Although significant progress in recent years has been made in defining key innate immune receptors involved in Alzheimer’s disease (AD), our knowledge of the specific intracellular signaling molecules that coordinate immune responses in AD remains poorly defined. In these studies, we have identified a previously undescribed role for the innate immune signaling molecule CARD9 in an amyloid beta (Ab)-mediated mouse model of AD. We specifically demonstrate that CARD9 deletion in the 5xFAD mouse model of AD leads to impaired control of Ab, worsened cognitive decline, and aberrant microglial activation. We further show that pharmacological activation of CARD9 provides a strategy to boost Ab clearance from the hippocampus. Collectively, these findings uncover a previously uncharacterized molecular signaling molecule used by the innate immune system in Ab-mediated neurological disease, and help to establish CARD9 as a novel molecular player that can be targeted in AD.

2023-05-23 | GSE232636 | GEO

CARD9 attenuates Aβ pathology and modifies microglial responses in an Alzheimer's disease mouse model.

Project description:Recent advances have highlighted the importance of several innate immune receptors expressed by microglia in Alzheimer's disease (AD). In particular, mounting evidence from AD patients and experimental models indicates pivotal roles for TREM2, CD33, and CD22 in neurodegenerative disease progression. While there is growing interest in targeting these microglial receptors to treat AD, we still lack knowledge of the downstream signaling molecules used by these receptors to orchestrate immune responses in AD. Notably, TREM2, CD33, and CD22 have been described to influence signaling associated with the intracellular adaptor molecule CARD9 to mount downstream immune responses outside of the brain. However, the role of CARD9 in AD remains poorly understood. Here, we show that genetic ablation of CARD9 in the 5xFAD mouse model of AD results in exacerbated amyloid beta (Aβ) deposition, increased neuronal loss, worsened cognitive deficits, and alterations in microglial responses. We further show that pharmacological activation of CARD9 promotes improved clearance of Aβ deposits from the brains of 5xFAD mice. These results help to establish CARD9 as a key intracellular innate immune signaling molecule that regulates Aβ-mediated disease and microglial responses. Moreover, these findings suggest that targeting CARD9 might offer a strategy to improve Aβ clearance in AD.

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Asrij/OCIAD1 depletion reduces inflammatory microglial activation and ameliorates Aβ pathology in an Alzheimer's disease mouse model

Project description:Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Ab) plaques and neurofibrillary tangles, neuroinflammation, and glial activation. Asrij/OCIAD1 (Ovarian Carcinoma Immunoreactive Antigen Domain containing protein 1) is an AD-associated factor. Increased Asrij levels in the brains of AD patients and mouse models are linked to the severity of neurodegeneration. However, the contribution of Asrij to AD progression and whether reducing Asrij levels is sufficient to mitigate Ab pathology in vivo is unclear. To explore the impact of Asrij on AD pathology, we deleted asrij in the APP/PS1 mouse model of AD and analyzed the effects on AD hallmarks. We find that Asrij depletion ameliorates cognitive impairments, Ab deposition, neuronal and synaptic damage, and reactive astrogliosis in the AD mouse. Emerging evidence indicates a critical role of microglia in influencing AD pathology. Notably, Asrij-deficient microglia exhibit reduced plaque-associated proliferation and decreased phagocytic activity. Transcriptomic analyses of AD microglia reveal upregulation of energy metabolism pathways and downregulation of innate immunity and inflammatory pathways upon Asrij depletion. Mechanistically, loss of Asrij increases mitochondrial activity and Akt/mTOR signaling and impedes the pro-inflammatory Disease-Associated Microglia (DAM) state. Reduced levels of pro-inflammatory cytokines and decreased STAT3 and NF-kB activation indicate protective changes in AD microglia. Taken together, our results suggest that increased Asrij levels reported in AD, may suppress microglial metabolic activity and promote inflammatory microglial activation, thereby exacerbating AD pathology. Our study establishes a novel role for Asrij in regulating microglial responses to Ab pathology, and could be a potential target for therapeutic intervention.

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Loss of PD-1 aggravates plaque pathology by disrupting microglial phagocytosis in APP/PS1 mice

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The VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer’s disease pathology

Project description:In Alzheimer’s disease (AD), sensome receptor dysfunction impairs microglial danger-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. While extrinsic signals including interleukin-33 (IL-33) can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor(s) is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aβ) plaque-associated ApoE, and leads to Aβ clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aβ-directed migration. Functional screening identified that VCAM1 directs microglial Aβ chemotaxis by sensing Aβ plaque-associated ApoE. Moreover, we found that disrupting VCAM1–ApoE interaction abolishes microglial Aβ chemotaxis, resulting in decreased microglial clearance of Aβ. In patients with AD, higher cerebrospinal fluid levels of soluble VCAM1 were correlated with impaired microglial Aβ chemotaxis. Together, our findings demonstrate that promoting VCAM1–ApoE-dependent microglial functions ameliorates AD pathology.

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Microglial microRNAs mediate sex-specific responses to tau pathology

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