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In this study, we utilized a multimodal approach, combining immunohistochemistry, functional metabolic mapping, and microstructure sensitive diffusion MRI (dMRI) to progressively investigate these interactions in the 5xFAD mouse model of AD. Our analysis revealed age-dependent and region-specific accumulation of key AD markers, including amyloid-beta (A\u03b2), GFAP, and IBA1, with significant differences observed between the hippocampal formation and upper and lower regions of the cortex by 6 months of age. Functional metabolic mapping validated localized disruptions in energy metabolism, with glucose hypometabolism in the hippocampus and impaired astrocytic metabolism in the cortex. Notably, increased cortical glutaminolysis suggested a shift in microglial metabolism, reflecting an adaptive response to neuroinflammatory processes. While dMRI showed no significant microstructural differences between 5xFAD and wild-type controls, the study highlights the importance of metabolic alterations as critical events in AD pathology. These findings emphasize the need for targeted therapeutic strategies addressing specific metabolic disturbances and underscore the potential of integrating advanced imaging with metabolic and molecular analyses to advance our understanding of AD progression.<\/jats:p>","DOI":"10.3390\/biom14101294","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T04:02:58Z","timestamp":1728878578000},"page":"1294","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Comprehensive Analysis of the 5xFAD Mouse Model of Alzheimer\u2019s Disease Using dMRI, Immunohistochemistry, and Neuronal and Glial Functional Metabolic Mapping"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6522-3916","authenticated-orcid":false,"given":"Emil W.","family":"Westi","sequence":"first","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0156-0870","authenticated-orcid":false,"given":"Saba","family":"Molhemi","sequence":"additional","affiliation":[{"name":"Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline Term\u00f8hlen","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0639-6718","authenticated-orcid":false,"given":"Christian Stald","family":"Skoven","sequence":"additional","affiliation":[{"name":"Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5475-6397","authenticated-orcid":false,"given":"Rasmus West","family":"Knopper","sequence":"additional","affiliation":[{"name":"Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark"},{"name":"Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, Beijing 100040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2539-9500","authenticated-orcid":false,"given":"Dashne Amein","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja B.","family":"Rindsh\u00f8j","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aishat O.","family":"Ameen","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Hansen","sequence":"additional","affiliation":[{"name":"Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0183-3816","authenticated-orcid":false,"given":"Kristi A.","family":"Kohlmeier","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca I.","family":"Aldana","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41572-021-00269-y","article-title":"Alzheimer disease","volume":"7","author":"Knopman","year":"2021","journal-title":"Nat. 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