{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:35:06Z","timestamp":1785418506971,"version":"3.56.0"},"reference-count":36,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008078","name":"University of Strathclyde","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008078","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00n3w3b69","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is the most prevalent form of dementia and is characterized by abnormal aggregation of \u03b2-amyloid (A\u03b2) peptides, tau proteins, and neuroinflammation in the central nervous system (CNS). While most AD research has focused on the brain, the molecular pathology of the spinal cord remains poorly understood. In this study, we investigated amyloid pathology, neurodegeneration, neuroinflammation, and cholesterol metabolism across distinct regions of the spinal cord and examined sex-specific differences using a model of AD, 5xFAD mice. Our data reveal that A\u03b2 accumulation was restricted to the cervical spinal cord at 3 months but was evident in all areas of the spinal cord by 9 months, with similar patterns in both female and male animals. Despite this early and progressive A\u03b2 deposition, no significant neuronal loss was observed in the ventral horn of the cervical spinal cord in either sex at 3 or 9 months of age. In contrast, there was a significant positive correlation between A\u03b2 deposition and Iba1+ cell density in the spinal cord of 5xFAD mice. The number of Iba1+ cells in both the grey and white matter was significantly increased in female and male 5xFAD mice compared with age-matched wild-type (WT) littermates at 9 months of age. Astrocytic responses, however, were sex-specific: female, but not male, 5xFAD mice exhibited a significant increase in GFAP+ astrocytes in the grey matter of the thoracic and lumber spinal cord at 9 months compared with 3 months and relative to age-matched WT controls in the cervical and thoracic spinal cord. Furthermore, GFAP+ area in the thoracic spinal cord was significantly higher in female 9-month-old 5xFAD mice compared with their male counterparts, indicating a female-specific astrocytic response in AD spinal cord pathology. Our data also show an increase in free cholesterol (Filipin+ area) in 5xFAD mice at 9 months relative to WT controls, accompanied by altered expression of cholesterol metabolism genes, including downregulation of Abca1, Cyp46a1 and Cyp27a1. Collectively, these findings provide new insights into AD progression in the spinal cord, highlighting molecular pathology of AD extending beyond the brain.<\/jats:p>","DOI":"10.3390\/ijms27083593","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T14:24:51Z","timestamp":1776435891000},"page":"3593","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Alzheimer\u2019s Spinal Pathology: Neuronal, Glial, and Cholesterol Metabolic Changes in Female and Male 5xFAD Mice"],"prefix":"10.3390","volume":"27","author":[{"given":"Xiaochuan","family":"Wang","sequence":"first","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Harnett","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3760-3019","authenticated-orcid":false,"given":"Xinhua","family":"Shu","sequence":"additional","affiliation":[{"name":"Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5753-0091","authenticated-orcid":false,"given":"Hui-Rong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"(2024). 2024 Alzheimer\u2019s disease facts and figures. 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