Macrophage NFATC2 mediates angiogenic signaling during mycobacterial infection

Brewer, W. Jared; Xet-Mull, Ana M.; Yu, Anne; Sweeney, Mollie I; Walton, Eric M; Tobin, David M.

doi:10.1016/j.celrep.2022.111817

Cited by 10 publications

(7 citation statements)

References 108 publications

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“…These findings suggest that overactivation of NMDARs may trigger DKK3 release. Consistent with this suggestion, treatment with BFA, an inhibitor of vesicle transport used to study the release of proteins ( Brewer et al, 2022 ; He et al, 2015 ; Katsinelos et al, 2018 ), blocks the increase in extracellular levels of DKK3 after cLTD. Given that LTD is increased in AD, these results suggest a possible mechanism for the regulation of DKK3 secretion in this condition.…”

Section: Discussionsupporting

confidence: 53%

“…Similar results were obtained using brain slices after cLTD-induction ( Figure 2—figure supplement 3C ). To test if the increase in extracellular DKK3 was due to changes in vesicular trafficking of DKK3, we used brefeldin A (BFA), which interrupts vesicle trafficking and exocytosis ( Brewer et al, 2022 ; He et al, 2015 ; Katsinelos et al, 2018 ). We found that BFA treatment significantly reduced DKK3 levels in the extracellular space under control conditions and completely prevented the increase in DKK3 levels following cLTD-induction ( Figure 2—figure supplement 3C ).…”

Section: Resultsmentioning

confidence: 99%

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Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer’s disease, restores synapse integrity and memory in a disease mouse model

Martin Flores,

Podpolny,

McLeod

et al. 2024

eLife

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Increasing evidence supports a role for deficient Wnt signaling in Alzheimer’s disease (AD). Studies reveal that the secreted Wnt antagonist Dickkopf-3 (DKK3) colocalizes to amyloid plaques in AD patients. Here, we investigate the contribution of DKK3 to synapse integrity in healthy and AD brains. Our findings show that DKK3 expression is upregulated in the brains of AD subjects and that DKK3 protein levels increase at early stages in the disease. In hAPP- J20 and hAPPNL-G-F/NL-G-F AD models, extracellular DKK3 levels are increased and DKK3 accumulates at dystrophic neuronal processes around plaques. Functionally, DKK3 triggers the loss of excitatory synapses through blockade of the Wnt/GSK3β signaling with a concomitant increase in inhibitory synapses signaling via activation of the Wnt/JNK pathway. In contrast, DKK3 knockdown restores synapse number and memory in hAPP-J20 mice. Collectively, our findings identify DKK3 as a novel driver of synaptic defects and memory impairment in AD.

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Section: Discussionsupporting

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer’s disease, restores synapse integrity and memory in a disease mouse model

Martin Flores,

Podpolny,

McLeod

et al. 2024

eLife

View full text Add to dashboard Cite

show abstract

“…Similar results were obtained using brain slices after cLTD-induction ( Figure S3C ). To test if the increase in extracellular DKK3 was due to changes in vesicular trafficking of DKK3, we used brefeldin A (BFA), which interrupts vesicle trafficking and exocytosis (Brewer et al, 2022; He et al, 2015; Katsinelos et al, 2018). We found that BFA treatment significantly reduced DKK3 levels in the extracellular space under control conditions and completely prevented the increase in DKK3 levels following cLTD-induction ( Figure S3C ).…”

Section: Resultsmentioning

confidence: 99%

Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer’s disease, restores synapse integrity and memory in a disease mouse model

Martín‐Flores

Podpolny

McLeod

et al. 2022

Preprint

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Increasing evidence supports a role of deficient Wnt signaling in Alzheimer's disease (AD). Recent studies reveal that the secreted Wnt antagonist Dickkopf-3 (DKK3) is elevated in the human AD brain. Here, we investigate the contribution of DKK3 to synapse integrity in the healthy and AD brain. We uncover a novel genetic link between DKK3 gene variants and AD risk. Our findings show that DKK3 protein is increased in different human brain fractions consistent with disease progression. In the hAPP-J20 and hAPPNL-G-F/NL-G-F AD models, DKK3 accumulates at plaques in the brain. Oligomers of amyloid-beta enhance the secretion of DKK3 from cultured neurons and DKK3 secretion is also increased in hippocampal slices of hAPP-J20 mice. In addition, gain-of-function experiments revealed that DKK3 decreases the density of excitatory synapses through inhibition of the canonical Wnt/GSK3beta pathway but increases inhibitory synapse density through activation of the Wnt/JNK pathway. Our studies demonstrate that in vivo DKK3 downregulation restores synapse number in hAPP-J20 mice. Importantly, DKK3 knockdown improves memory in this AD model. Collectively, our findings identify DKK3 as a novel driver of synapse defects and memory impairment in AD.

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“…Using adult zebrafish in infection studies has helped build our understanding of the role of adaptive immune responses to mycobacterial infection (Swaim et al, 2006) and could lead to the development of improved vaccines for tuberculosis (Saralahti et al, 2020). Furthermore, introducing mutations or knockout of key immune signalling molecules to adult zebrafish has dissected the complexity of immune responses to M. marinum infection (Brewer et al, 2022), including more-unique features, such as granuloma formation (Cronan et al, 2021), that are conserved in tuberculosis in humans (Ramakrishnan, 2023).…”

Section: Gene-environment Interactions In Adult Zebrafishmentioning

confidence: 99%

Adult zebrafish as advanced models of human disease

White

Patton

2023

Disease Models &Amp; Mechanisms

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Modelling adult diseases to understand their aetiology and progression, and to develop new therapies, is a major challenge for medical biology. We are excited by new efforts in the zebrafish community to develop models of adult diseases that range from cancer to heart, infectious and age-related diseases, and those that relate to toxicology and complex social behaviours. Here, we discuss some of the advances in the field of zebrafish models of adult disease, and where we see opportunities and challenges ahead.

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Macrophage NFATC2 mediates angiogenic signaling during mycobacterial infection

Cited by 10 publications

References 108 publications

Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer’s disease, restores synapse integrity and memory in a disease mouse model

Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer’s disease, restores synapse integrity and memory in a disease mouse model

Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer’s disease, restores synapse integrity and memory in a disease mouse model

Adult zebrafish as advanced models of human disease

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