{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:24:15Z","timestamp":1789190655851,"version":"build-2803163510"},"reference-count":72,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T00:00:00Z","timestamp":1743984000000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R01NS034239\u201029"],"award-info":[{"award-number":["5R01NS034239\u201029"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>INTRODUCTION<\/jats:title><jats:p>Transgenic mice overexpressing familial Alzheimer's disease (AD) mutations (FAD) show non\u2010physiological traits, and their immunocompetent backgrounds limit their use in AD immunotherapy research. Preclinical models that reflect human immune responses in AD are needed.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Using CRISPR\u2010Cas9, we developed single (NA) and double (NAPS) knock\u2010in (KI) amyloid precursor protein (APP)<jats:sup>KM670,671NL<\/jats:sup> (Swedish) and presenilin 1 (PS 1)<jats:sup>M146V<\/jats:sup>FAD mutations on an immunodeficient NOG (NOD.Cg\u2010Prkdc<jats:sup>scid<\/jats:sup>Il2rg<jats:sup>tm1Sug<\/jats:sup>\/JicTac) background. The models were confirmed by Sanger sequencing and evaluated for AD\u2010like pathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Both NA and NAPS mice developed pathology without overexpression artifacts. Mutation\u2010induced upregulation of APP\u2010CTF\u2010\u03b2 led to intraneuronal human amyloid beta (A\u03b2) (6E10) deposits and amyloid\u2010associated microgliosis as early as 3 months, which increased with age. The addition of the PS\u00a01<jats:sup>M146V<\/jats:sup> mutation doubled the amyloid load. The models displayed broad neuronal loss, resulting in brain atrophy in older mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>These models replicate intraneuronal amyloid pathology and, with human immune reconstitution potential, enable novel studies of human immune responses in AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>A novel Alzheimer's disease (AD) knock\u2010in (KI) mouse was developed and characterized on an immunodeficient NOG background. The model provides a platform for human immune studies and the evaluation of immunotherapies for AD.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The KI mice demonstrate intraneuronal A\u03b2 deposits and amyloid\u2010associated microglial reactions.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>KI mice demonstrate extensive neuronal loss.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Human immune reconstitution enables studies of infectious AD co\u2010morbidities, such as the human immunodeficiency and herpes simplex viruses.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.70084","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T03:30:48Z","timestamp":1744083048000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Amyloid precursor protein and presenilin\u20101 knock\u2010in immunodeficient mice exhibit intraneuronal A\u03b2 pathology, microgliosis, and extensive neuronal loss"],"prefix":"10.1002","volume":"21","author":[{"given":"Pravin","family":"Yeapuri","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience Center for Neurodegenerative Disorders College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jatin","family":"Machhi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience Center for Neurodegenerative Disorders College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma G.","family":"Foster","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience Center for Neurodegenerative Disorders College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana","family":"Kadry","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience Center for Neurodegenerative Disorders College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaurav","family":"Bhattarai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience Center for Neurodegenerative Disorders College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaman","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience Center for Neurodegenerative Disorders College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susmita","family":"Sil","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience Center for Neurodegenerative Disorders College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roshan","family":"Sapkota","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience Center for Neurodegenerative Disorders College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shefali","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience Center for Neurodegenerative Disorders College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohit","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience Center for Neurodegenerative Disorders College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuneya","family":"Ikezu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Mayo Clinic Florida  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larisa Y.","family":"Poluektova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience Center for Neurodegenerative Disorders College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard E.","family":"Gendelman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience Center for Neurodegenerative Disorders College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney Lee","family":"Mosley","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience Center for Neurodegenerative Disorders College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,7]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-016-1662-x"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-018-0054-8"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-017-0231-7"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12114"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000006745"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12050"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-017-1729-4"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12213"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40259-023-00633-2"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1389-0344(01)00067-3"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.867015"},{"key":"e_1_2_10_13_1","first-page":"433","article-title":"Differences in innate immune response between man and mouse","volume":"34","author":"Zschaler J","year":"2014","journal-title":"Crit Rev Immunol"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.02.001"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-021-00487-8"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ntt.2021.107056"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-021-00582-x"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3697"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201797397"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.5.2731"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-021-00549-x"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-020-00375-7"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-021-02308-7"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-023-00692-7"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01892-1"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/btm2.10378"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-021-02508-5"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0311-y"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-74359-8"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3820"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0439-x"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.14806\/ej.17.1.200"},{"key":"e_1_2_10_33_1","unstructured":"AndrewsS.FastQC: A quality control tool for high throughput sequence data.http:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/ed2010"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-323"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.3162"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/360672a0"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-6606-4-3"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01249-0"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/34910"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.2174\/138161212799315786"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-170045"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.115.171652"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-510X(97)05399-9"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2006.06.010"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(03)00252-0"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201709069"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-024-00712-0"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2016.01.002"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1009625323388"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4608"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2168"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.01.040"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00434-3"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1202-06.2006"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.050593"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-8-2"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-008-0451-6"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-183X.2007.00372.x"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22624-z"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1177\/03009858231151403"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(00)00124-X"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1895-7"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200947"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2019.05.039"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202207719"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaa112"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv408"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.75965"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-024-01880-3"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2018.00083"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1515\/nipt\u20102024\u20100018"}],"updated-by":[{"DOI":"10.1002\/alz.70534","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000}}],"container-title":["Alzheimer's &amp; Dementia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/alz.70084","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T20:59:30Z","timestamp":1759957170000},"score":1,"resource":{"primary":{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/10.1002\/alz.70084"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4]]},"references-count":72,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1002\/alz.70084"],"URL":"https:\/\/doi.org\/10.1002\/alz.70084","archive":["Portico"],"relation":{"correction":[{"id-type":"doi","id":"10.1002\/alz.70534","asserted-by":"object"}]},"ISSN":["1552-5260","1552-5279"],"issn-type":[{"value":"1552-5260","type":"print"},{"value":"1552-5279","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4]]},"assertion":[{"value":"2024-11-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70084"}}