{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T20:27:41Z","timestamp":1774988861355,"version":"3.50.1"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,19]],"date-time":"2022-02-19T00:00:00Z","timestamp":1645228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["- R01AG042178, R01AG47812, R01NS105473, AG060767, AG069333, and AG066347"],"award-info":[{"award-number":["- R01AG042178, R01AG47812, R01NS105473, AG060767, AG069333, and AG066347"]}]},{"name":"National Institute of Health","award":["K99AG065645"],"award-info":[{"award-number":["K99AG065645"]}]},{"name":"National Institute of Health","award":["AG063162"],"award-info":[{"award-number":["AG063162"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The purpose of our study is to investigate early cellular, molecular, morphological and behavioral changes in humanized amyloid-beta-knock-in (hAbKI) mice. Using seven-month-old homozygous hAbKI mice, we studied behavioral phenotype parameters, including spatial learning and memory (Morris Water Maze), locomotor activity (open field), working memory (Y-maze) and motor coordination (rotarod); mRNA abundance, protein levels, soluble amyloid-beta 40 and 42 levels and regional immunoreactivities of key markers of mitochondrial dynamics, mitochondrial biogenesis, synaptic health, mitophagy and autophagy; mitochondrial function and using transmission electron microscopy &amp; Golgi\u2013Cox staining, we assessed mitochondrial morphology and dendritic spines. Our extensive behavioral analysis revealed that seven-month-old hAbKI mice showed impairments in motor coordination, reduced locomotor and exploration activities, impairments in working memory and spatial learning and memory. Our mRNA and protein analyses revealed the increased expression of mitochondrial-fission genes and reduced expression of mitochondrial-fusion, mitochondrial-biogenesis, synaptic, autophagy and mitophagy genes in seven-month-old hAbKI mice. An immunofluorescence analysis revealed altered immunoreactivities and agreed with the immunoblot results. Transmission-electron-microscopy data revealed increased mitochondrial fragmentation and reduced mitochondrial length in both hippocampal and cortical tissues of seven-month-old hAbKI mice and mitochondrial function defective. A Golgi\u2013Cox-staining analysis revealed reduced dendritic spines in both cerebral cortices and hippocampi of hAbKI mice. Soluble amyloid-beta (1\u201340 and 1\u201342) were detected in three-month-old hAbKI mice and progressively increased in seven-month-old mice. These observations suggest that the human amyloid-beta peptide is sufficient to cause behavioral, mitochondrial, synaptic and ultrastructural changes in seven-month-old hAbKI mice. Our study findings also suggest that hAbKI mice might serve as a model for preclinical studies of preventive therapies.<\/jats:p>","DOI":"10.3390\/cells11040733","type":"journal-article","created":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T08:14:46Z","timestamp":1645431286000},"page":"733","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Early Cellular, Molecular, Morphological and Behavioral Changes in the Humanized Amyloid-Beta-Knock-In Mouse Model of Late-Onset Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2102-7459","authenticated-orcid":false,"given":"Sudhir","family":"Kshirsagar","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rainier Vladlen","family":"Alvir","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashly","family":"Hindle","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Subodh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7426-3415","authenticated-orcid":false,"given":"Murali","family":"Vijayan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jangampalli Adi","family":"Pradeepkiran","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arubala P.","family":"Reddy","sequence":"additional","affiliation":[{"name":"Nutritional Sciences Department, College of Human Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX 79409, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhagavathi","family":"Ramasubramanian","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9560-9948","authenticated-orcid":false,"given":"P. Hemachandra","family":"Reddy","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Neuroscience & Pharmacology Department, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Neurology, Departments of School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1152\/physrev.2001.81.2.741","article-title":"Alzheimer\u2019s disease: Genes, proteins, and therapy","volume":"81","author":"Selkoe","year":"2001","journal-title":"Physiol. 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