Manganese Exposure Aggravates β-Amyloid Pathology by Microglial Activation
Human epidemiological evidence and animal experimental data suggest that chronic manganese (Mn) exposure increases the risk of Alzheimer’s disease (AD) and amyloid plaques, a hallmark of AD brain pathology, but the underlying mechanisms were not fully understood. Using the transgenic APP/PS1/Tau tri...
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| Format: | Article |
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Frontiers Media S.A.
2020-11-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2020.556008/full |
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| author | Geng Lin Xinlu Li Xiaofeng Cheng Ning Zhao Wei Zheng |
| author_facet | Geng Lin Xinlu Li Xiaofeng Cheng Ning Zhao Wei Zheng |
| author_sort | Geng Lin |
| collection | DOAJ |
| description | Human epidemiological evidence and animal experimental data suggest that chronic manganese (Mn) exposure increases the risk of Alzheimer’s disease (AD) and amyloid plaques, a hallmark of AD brain pathology, but the underlying mechanisms were not fully understood. Using the transgenic APP/PS1/Tau triple transgenic AD (3×Tg-AD) mouse model and mouse-derived microglia and neuroblastoma cell lines, we found that chronic 5-month Mn treatment increased beta amyloid peptide (Aβ) expression and Aβ plaques in the cerebral cortex and hippocampus in these 3×Tg-AD mice. Furthermore, we found that the β- and γ-secretase cleavage activities were markedly increased, while α-secretase cleavage activity was reduced in the brain of Mn-treated AD mice; these effects increase Aβ production and thus are amyloidogenic. Equally important, Mn treatment alone did not alter β-secretase 1 (BACE1) gene expression or Aβ production in amyloidogenic mutant amyloid precursor protein (APP) gene hAPPsw-transfected N2a cells (APPsw-N2a), but in APPsw-N2a cells either co-cultured with microglia or cultured with microglia-conditioned media, Mn exposure increased BACE1 expression and amyloidogenesis. We further determined that Mn exposure promoted the activation of microglia both in 3×Tg-AD mouse brains and in cultured microglia cells, and increased the secretion of the inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Taken together, these results suggest that Mn may increase the release of IL-1β and TNF-α from microglia that in turn stimulates the expression of BACE1 gene and protein and consequently Aβ production; this novel molecular mechanism not only advances our understanding about the amyloidogenic effect of chronic Mn exposure reported for special human populations but also indicates Mn dyshomeostasis as a potential contributor to AD pathogenesis. |
| first_indexed | 2024-12-12T00:28:49Z |
| format | Article |
| id | doaj.art-c66c97237ad14fcaa321d1253b151c8d |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-12-12T00:28:49Z |
| publishDate | 2020-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-c66c97237ad14fcaa321d1253b151c8d2022-12-22T00:44:33ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652020-11-011210.3389/fnagi.2020.556008556008Manganese Exposure Aggravates β-Amyloid Pathology by Microglial ActivationGeng Lin0Xinlu Li1Xiaofeng Cheng2Ning Zhao3Wei Zheng4Department of Histology and Embryology, China Medical University, Shenyang, ChinaDepartment of Histology and Embryology, China Medical University, Shenyang, ChinaDepartment of Histology and Embryology, China Medical University, Shenyang, ChinaShengjing Hospital of China Medical University, Shenyang, ChinaDepartment of Histology and Embryology, China Medical University, Shenyang, ChinaHuman epidemiological evidence and animal experimental data suggest that chronic manganese (Mn) exposure increases the risk of Alzheimer’s disease (AD) and amyloid plaques, a hallmark of AD brain pathology, but the underlying mechanisms were not fully understood. Using the transgenic APP/PS1/Tau triple transgenic AD (3×Tg-AD) mouse model and mouse-derived microglia and neuroblastoma cell lines, we found that chronic 5-month Mn treatment increased beta amyloid peptide (Aβ) expression and Aβ plaques in the cerebral cortex and hippocampus in these 3×Tg-AD mice. Furthermore, we found that the β- and γ-secretase cleavage activities were markedly increased, while α-secretase cleavage activity was reduced in the brain of Mn-treated AD mice; these effects increase Aβ production and thus are amyloidogenic. Equally important, Mn treatment alone did not alter β-secretase 1 (BACE1) gene expression or Aβ production in amyloidogenic mutant amyloid precursor protein (APP) gene hAPPsw-transfected N2a cells (APPsw-N2a), but in APPsw-N2a cells either co-cultured with microglia or cultured with microglia-conditioned media, Mn exposure increased BACE1 expression and amyloidogenesis. We further determined that Mn exposure promoted the activation of microglia both in 3×Tg-AD mouse brains and in cultured microglia cells, and increased the secretion of the inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Taken together, these results suggest that Mn may increase the release of IL-1β and TNF-α from microglia that in turn stimulates the expression of BACE1 gene and protein and consequently Aβ production; this novel molecular mechanism not only advances our understanding about the amyloidogenic effect of chronic Mn exposure reported for special human populations but also indicates Mn dyshomeostasis as a potential contributor to AD pathogenesis.https://www.frontiersin.org/articles/10.3389/fnagi.2020.556008/fullAlzheimer’s diseaseβ-amyloidmicrogliamanganeseneuroinflammationcytokines |
| spellingShingle | Geng Lin Xinlu Li Xiaofeng Cheng Ning Zhao Wei Zheng Manganese Exposure Aggravates β-Amyloid Pathology by Microglial Activation Frontiers in Aging Neuroscience Alzheimer’s disease β-amyloid microglia manganese neuroinflammation cytokines |
| title | Manganese Exposure Aggravates β-Amyloid Pathology by Microglial Activation |
| title_full | Manganese Exposure Aggravates β-Amyloid Pathology by Microglial Activation |
| title_fullStr | Manganese Exposure Aggravates β-Amyloid Pathology by Microglial Activation |
| title_full_unstemmed | Manganese Exposure Aggravates β-Amyloid Pathology by Microglial Activation |
| title_short | Manganese Exposure Aggravates β-Amyloid Pathology by Microglial Activation |
| title_sort | manganese exposure aggravates β amyloid pathology by microglial activation |
| topic | Alzheimer’s disease β-amyloid microglia manganese neuroinflammation cytokines |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2020.556008/full |
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