{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T07:48:02Z","timestamp":1782200882179,"version":"3.54.5"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-ES-026591"],"award-info":[{"award-number":["R01-ES-026591"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32-ES-007032"],"award-info":[{"award-number":["T32-ES-007032"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Environmental Health Sciences","award":["R01-ES-026591"],"award-info":[{"award-number":["R01-ES-026591"]}]},{"name":"National Institute of Environmental Health Sciences","award":["T32-ES-007032"],"award-info":[{"award-number":["T32-ES-007032"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The apolipoprotein E (ApoE) gene is a genetic risk factor for late-onset Alzheimer\u2019s disease, in which \u03b54 allele carriers have increased risk compared to the common \u03b53 carriers. Cadmium (Cd) is a toxic heavy metal and a potential neurotoxicant. We previously reported a gene\u2013environment interaction (GxE) effect between ApoE4 and Cd that accelerates or increases the severity of the cognitive decline in ApoE4-knockin (ApoE4-KI) mice exposed to 0.6 mg\/L CdCl2 through drinking water compared to control ApoE3-KI mice. However, the mechanisms underlying this GxE effect are not yet defined. Because Cd impairs adult neurogenesis, we investigated whether genetic and conditional stimulation of adult neurogenesis can functionally rescue Cd-induced cognitive impairment in ApoE4-KI mice. We crossed either ApoE4-KI or ApoE3-KI to an inducible Cre mouse strain, Nestin-CreERTM:caMEK5-eGFPloxP\/loxP (designated as caMEK5), to generate ApoE4-KI:caMEK5 and ApoE3-KI:caMEK5. Tamoxifen administration in these mice genetically and conditionally induces the expression of caMEK5 in adult neural stem\/progenitor cells, enabling the stimulation of adult neurogenesis in the brain. Male ApoE4-KI:caMEK5 and ApoE3-KI:caMEK5 mice were exposed to 0.6 mg\/L CdCl2 throughout the experiment, and tamoxifen was administered once Cd-induced impairment in spatial working memory was consistently observed. Cd exposure impaired spatial working memory earlier in ApoE4-KI:caMEK5 than in ApoE3-KI:caMEK5 mice. In both strains, these deficits were rescued after tamoxifen treatment. Consistent with these behavioral findings, tamoxifen treatment enhanced adult neurogenesis by increasing the morphological complexity of adult-born immature neurons. These results provide evidence for a direct link between impaired spatial memory and adult neurogenesis in this GxE model.<\/jats:p>","DOI":"10.3390\/ijms24119118","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T03:20:06Z","timestamp":1684812006000},"page":"9118","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Inducible and Conditional Activation of Adult Neurogenesis Rescues Cadmium-Induced Hippocampus-Dependent Memory Deficits in ApoE4-KI Mice"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6874-0836","authenticated-orcid":false,"given":"Megumi T.","family":"Matsushita","sequence":"first","affiliation":[{"name":"Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7134-7138","authenticated-orcid":false,"given":"Hao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glen M.","family":"Abel","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengui","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"(2022). 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