Congcong Wang

All Publications

• TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models. Nature neuroscience Wilson, E. N., Wang, C., Swarovski, M. S., Zera, K. A., Ennerfelt, H. E., Wang, Q., Chaney, A., Gauba, E., Ramos Benitez, J. A., Le Guen, Y., Minhas, P. S., Panchal, M., Tan, Y. J., Blacher, E., A Iweka, C., Cropper, H., Jain, P., Liu, Q., Mehta, S. S., Zuckerman, A. J., Xin, M., Umans, J., Huang, J., Durairaj, A. S., Serrano, G. E., Beach, T. G., Greicius, M. D., James, M. L., Buckwalter, M. S., McReynolds, M. R., Rabinowitz, J. D., Andreasson, K. I. 2024

  Abstract

  Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-β42 oligomer-induced bioenergetic changes, suggesting that amyloid-β42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.

  View details for DOI 10.1038/s41593-024-01610-w

  View details for PubMedID 38539014

  View details for PubMedCentralID 4369837

• Odorant receptors in macrophages: potential targets for atherosclerosis. Trends in immunology Wang, C., Andreasson, K. I. 2022

  Abstract

  In a recent report, Orecchioni et al. identify a role for the olfactory receptor (OR) Olfr2 and its human ortholog OR6A2 in atherosclerosis. Vascular macrophage Olfr2 binds octanal, a product of lipid peroxidation, activating the NLRP3 inflammasome and IL-1beta secretion, and driving atherosclerosis pathology. Thus, OR6A2 inhibitors may represent a promising therapy for atherosclerosis.

  View details for DOI 10.1016/j.it.2022.02.006

  View details for PubMedID 35283015

• Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature Minhas, P. S., Latif-Hernandez, A., McReynolds, M. R., Durairaj, A. S., Wang, Q., Rubin, A., Joshi, A. U., He, J. Q., Gauba, E., Liu, L., Wang, C., Linde, M., Sugiura, Y., Moon, P. K., Majeti, R., Suematsu, M., Mochly-Rosen, D., Weissman, I. L., Longo, F. M., Rabinowitz, J. D., Andreasson, K. I. 2021

  Abstract

  Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1-3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease4-6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.

  View details for DOI 10.1038/s41586-020-03160-0

  View details for PubMedID 33473210