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Chronic copper exposure directs microglia towards degenerative expression signatures in wild-type and J20 mouse model of Alzheimer's disease.
J Trace Elem Med Biol. 2020 Jun 20; 62:126578.JT

Abstract

BACKGROUND

Copper (Cu) is an essential metal mediating a variety of vital biological reactions with its redox property. Its dyshomeostasis has been associated with accelerated cognitive decline and neurodegenerative disorders, such as Alzheimer's disease (AD). However, underlying neurotoxic mechanisms elicited by dysregulated Cu remain largely elusive. We and others previously demonstrated that exposure to Cu in drinking water significantly exacerbated pathological hallmarks of AD and pro-inflammatory activation of microglia, coupled with impaired phagocytic capacity, in mouse models of AD.

METHODS

In the present study, we extended our investigation to evaluate whether chronic Cu exposure to wild-type (WT) and J20 mouse model of AD perturbs homeostatic dynamics of microglia and contributes to accelerated transformation of microglia towards degenerative phenotypes that are closely associated with neurodegeneration. We further looked for evidence of alterations in the microglial morphology and spatial memory of the Cu-exposed mice to assess the extent of the Cu toxicity.

RESULTS

We find that chronic Cu exposure to pre-pathological J20 mice upregulates the translation of degenerative genes and represses homeostatic genes within microglia even in the absence amyloid-beta plaques. We also observe similar expression signatures in Cu-exposed WT mice, suggesting that excess Cu exposure alone could lead to perturbed microglial homeostatic phenotypes and contribute to accelerated cognitive decline.

CONCLUSION

Our findings highlight the risk of chronic Cu exposure on cognitive decline and altered microglia activation towards degenerative phenotypes. These changes may represent one of the key mechanisms linking Cu exposure or its dyshomeostasis to an increased risk for AD.

Authors+Show Affiliations

Center for Occupational and Environmental Health, Department of Medicine, University of California, Irvine, CA, USA.Center for Occupational and Environmental Health, Department of Medicine, University of California, Irvine, CA, USA.Center for Occupational and Environmental Health, Department of Medicine, University of California, Irvine, CA, USA.Department of Biological Chemistry, University of California, Irvine, CA, USA.Center for Occupational and Environmental Health, Department of Medicine, University of California, Irvine, CA, USA.Center for Occupational and Environmental Health, Department of Medicine, University of California, Irvine, CA, USA.Center for Occupational and Environmental Health, Department of Medicine, University of California, Irvine, CA, USA.Nash Family Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, NY, USA.Center for Occupational and Environmental Health, Department of Medicine, University of California, Irvine, CA, USA. Electronic address: kitazawa@uci.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32599538

Citation

Lim, Siok Lam, et al. "Chronic Copper Exposure Directs Microglia Towards Degenerative Expression Signatures in Wild-type and J20 Mouse Model of Alzheimer's Disease." Journal of Trace Elements in Medicine and Biology : Organ of the Society for Minerals and Trace Elements (GMS), vol. 62, 2020, p. 126578.
Lim SL, Rodriguez-Ortiz CJ, Hsu HW, et al. Chronic copper exposure directs microglia towards degenerative expression signatures in wild-type and J20 mouse model of Alzheimer's disease. J Trace Elem Med Biol. 2020;62:126578.
Lim, S. L., Rodriguez-Ortiz, C. J., Hsu, H. W., Wu, J., Zumkehr, J., Kilian, J., Vidal, J., Ayata, P., & Kitazawa, M. (2020). Chronic copper exposure directs microglia towards degenerative expression signatures in wild-type and J20 mouse model of Alzheimer's disease. Journal of Trace Elements in Medicine and Biology : Organ of the Society for Minerals and Trace Elements (GMS), 62, 126578. https://doi.org/10.1016/j.jtemb.2020.126578
Lim SL, et al. Chronic Copper Exposure Directs Microglia Towards Degenerative Expression Signatures in Wild-type and J20 Mouse Model of Alzheimer's Disease. J Trace Elem Med Biol. 2020 Jun 20;62:126578. PubMed PMID: 32599538.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chronic copper exposure directs microglia towards degenerative expression signatures in wild-type and J20 mouse model of Alzheimer's disease. AU - Lim,Siok Lam, AU - Rodriguez-Ortiz,Carlos J, AU - Hsu,Heng-Wei, AU - Wu,Jie, AU - Zumkehr,Joannee, AU - Kilian,Jason, AU - Vidal,Janielle, AU - Ayata,Pinar, AU - Kitazawa,Masashi, Y1 - 2020/06/20/ PY - 2020/01/26/received PY - 2020/05/24/revised PY - 2020/06/05/accepted PY - 2020/7/1/pubmed PY - 2020/7/1/medline PY - 2020/6/30/entrez KW - Alzheimer’s disease KW - Copper KW - Microglia KW - Translating ribosome affinity purification (TRAP) KW - Translatome SP - 126578 EP - 126578 JF - Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) JO - J Trace Elem Med Biol VL - 62 N2 - BACKGROUND: Copper (Cu) is an essential metal mediating a variety of vital biological reactions with its redox property. Its dyshomeostasis has been associated with accelerated cognitive decline and neurodegenerative disorders, such as Alzheimer's disease (AD). However, underlying neurotoxic mechanisms elicited by dysregulated Cu remain largely elusive. We and others previously demonstrated that exposure to Cu in drinking water significantly exacerbated pathological hallmarks of AD and pro-inflammatory activation of microglia, coupled with impaired phagocytic capacity, in mouse models of AD. METHODS: In the present study, we extended our investigation to evaluate whether chronic Cu exposure to wild-type (WT) and J20 mouse model of AD perturbs homeostatic dynamics of microglia and contributes to accelerated transformation of microglia towards degenerative phenotypes that are closely associated with neurodegeneration. We further looked for evidence of alterations in the microglial morphology and spatial memory of the Cu-exposed mice to assess the extent of the Cu toxicity. RESULTS: We find that chronic Cu exposure to pre-pathological J20 mice upregulates the translation of degenerative genes and represses homeostatic genes within microglia even in the absence amyloid-beta plaques. We also observe similar expression signatures in Cu-exposed WT mice, suggesting that excess Cu exposure alone could lead to perturbed microglial homeostatic phenotypes and contribute to accelerated cognitive decline. CONCLUSION: Our findings highlight the risk of chronic Cu exposure on cognitive decline and altered microglia activation towards degenerative phenotypes. These changes may represent one of the key mechanisms linking Cu exposure or its dyshomeostasis to an increased risk for AD. SN - 1878-3252 UR - https://www.unboundmedicine.com/medline/citation/32599538/Chronic_copper_exposure_directs_microglia_towards_degenerative_expression_signatures_in_wild-type_and_J20_mouse_model_of_Alzheimer's_disease L2 - https://linkinghub.elsevier.com/retrieve/pii/S0946-672X(20)30143-7 DB - PRIME DP - Unbound Medicine ER -
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