{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T05:17:28Z","timestamp":1788499048799,"version":"build-2803163510"},"reference-count":79,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program","doi-asserted-by":"publisher","award":["2021YFF0702201"],"award-info":[{"award-number":["2021YFF0702201"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guangzhou Key Research Program on Brain Science","award":["202007030008"],"award-info":[{"award-number":["202007030008"]}]},{"DOI":"10.13039\/501100007162","name":"Department of Science and Technology of Guangdong Province","doi-asserted-by":"publisher","award":["2021A1515012526"],"award-info":[{"award-number":["2021A1515012526"]}],"id":[{"id":"10.13039\/501100007162","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2021A1515012526"],"award-info":[{"award-number":["2021A1515012526"]}],"id":[{"id":"https:\/\/ror.org\/00tjzgn92","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82394422"],"award-info":[{"award-number":["82394422"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81830032"],"award-info":[{"award-number":["81830032"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81873736"],"award-info":[{"award-number":["81873736"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82394422"],"award-info":[{"award-number":["82394422"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["81830032"],"award-info":[{"award-number":["81830032"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["81873736"],"award-info":[{"award-number":["81873736"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Tau pathology is a hallmark feature of Alzheimer\u2019s disease (AD) and is tightly associated with clinical manifestations. No disease-modifying therapy is currently available for AD, partly due to prominent interspecies differences in tau expression patterns between rodents and primates. To facilitate the investigation of primate-specific tau pathology, we developed an in vitro platform using monkey (Macaca fascicularis) brain slice cultures (BSC) that preserve native three-dimensional tissue architecture and maintain functional networks closely mirroring in vivo conditions. We systematically evaluated various adeno-associated virus (AAV) serotypes and promoter combinations to achieve efficient transgenic tau expression. Our data confirm that the monkey BSC system is highly amenable to AAV-mediated gene delivery, exhibiting robust transduction of glial cells with minimal cytotoxicity and allowing for the examination of glial pathology induced by disease-associated proteins. Notably, this platform is applicable to both juvenile and aged specimens, enabling comparative analyses of age-dependent susceptibility to pathological insults. Following overexpression of mutant human tau, we observed time-dependent tau pathology development within 2\u20134 weeks post-infection, including hyperphosphorylation and aggregation. This in vitro primate model offers a unique opportunity to dissect primate-specific pathological events. Furthermore, the scalability and reproducibility of this system render it ideally suited for drug screening, providing a more translationally relevant preclinical bridge between rodent models and human clinical trials.<\/jats:p>","DOI":"10.3390\/biology15171496","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T07:53:11Z","timestamp":1788335591000},"page":"1496","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modeling Tau-Mediated Pathology in Monkey Brain Slices"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8903-6482","authenticated-orcid":false,"given":"Mingtian","family":"Pan","sequence":"first","affiliation":[{"name":"Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Lingang Laboratory, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Qintian","family":"Guo","sequence":"additional","affiliation":[{"name":"Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Peisi","family":"Huang","sequence":"additional","affiliation":[{"name":"Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Xiang","family":"Han","sequence":"additional","affiliation":[{"name":"Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6620-469X","authenticated-orcid":false,"given":"Sitong","family":"Yang","sequence":"additional","affiliation":[{"name":"Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7582-3157","authenticated-orcid":false,"given":"Fengwei","family":"Sun","sequence":"additional","affiliation":[{"name":"Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Jiawei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"Laiqiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Bang","family":"Li","sequence":"additional","affiliation":[{"name":"Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"given":"Dajian","family":"He","sequence":"additional","affiliation":[{"name":"Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Lingang Laboratory, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1775-6536","authenticated-orcid":false,"given":"Shihua","family":"Li","sequence":"additional","affiliation":[{"name":"Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9370-8838","authenticated-orcid":false,"given":"Xiao-Jiang","family":"Li","sequence":"additional","affiliation":[{"name":"Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2960-839X","authenticated-orcid":false,"given":"Xiangyu","family":"Guo","sequence":"additional","affiliation":[{"name":"Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e71066","DOI":"10.1002\/alz.71066","article-title":"Alzheimer\u2019s disease polygenic risk in early- and late-onset Alzheimer\u2019s disease","volume":"22","author":"Pentchev","year":"2026","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7337","DOI":"10.1016\/j.cell.2025.11.033","article-title":"The evolving landscape of Alzheimer\u2019s disease therapy: From Abeta to tau","volume":"188","author":"Courade","year":"2025","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"(2023). 2023 Alzheimer\u2019s disease facts and figures. Alzheimer\u2019s Dement. J. Alzheimer\u2019s Assoc., 19, 1598\u20131695.","DOI":"10.1002\/alz.13016"},{"key":"ref_4","unstructured":"Collaborators GBDPsD (2018). Global, regional, and national burden of Parkinson\u2019s disease, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol., 17, 939\u2013953."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Cui, L., Hou, N.N., Wu, H.M., Zuo, X., Lian, Y.Z., Zhang, C.N., Wang, Z.F., Zhang, X., and Zhu, J.H. (2020). Prevalence of Alzheimer\u2019s Disease and Parkinson\u2019s Disease in China: An Updated Systematical Analysis. Front. Aging Neurosci., 12.","DOI":"10.3389\/fnagi.2020.603854"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1016\/S0140-6736(25)01389-3","article-title":"Alzheimer\u2019s disease outlook: Controversies and future directions","volume":"406","author":"Frisoni","year":"2025","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1093\/procel\/pwae026","article-title":"Alzheimer\u2019s disease: Insights into pathology, molecular mechanisms, and therapy","volume":"16","author":"Zheng","year":"2025","journal-title":"Protein Cell"},{"key":"ref_8","first-page":"1244","article-title":"Understanding Tau pathology: Insights from animal models","volume":"46","author":"Zhang","year":"2025","journal-title":"Zool. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1016\/j.stem.2022.09.010","article-title":"A single-cell transcriptome atlas of glial diversity in the human hippocampus across the postnatal lifespan","volume":"29","author":"Su","year":"2022","journal-title":"Cell Stem Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"105994","DOI":"10.1016\/j.nbd.2023.105994","article-title":"Disrupted axon-glia communication leads to neurodegeneration in metabolic diseases","volume":"177","author":"Sakowski","year":"2023","journal-title":"Neurobiol. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4153","DOI":"10.1016\/j.cell.2022.09.033","article-title":"TREM2 drives microglia response to amyloid-beta via SYK-dependent and -independent pathways","volume":"185","author":"Wang","year":"2022","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1038\/s41593-018-0242-x","article-title":"Microglia in neurodegeneration","volume":"21","author":"Hickman","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1038\/s41593-020-00728-x","article-title":"Tau accumulation in astrocytes of the dentate gyrus induces neuronal dysfunction and memory deficits in Alzheimer\u2019s disease","volume":"23","author":"Richetin","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41573-022-00390-x","article-title":"Function and therapeutic value of astrocytes in neurological diseases","volume":"21","author":"Lee","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1007\/s00429-017-1383-5","article-title":"Human astrocytes: Structure and functions in the healthy brain","volume":"222","author":"Vasile","year":"2017","journal-title":"Brain Struct. Funct."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.tins.2006.08.004","article-title":"Astrocytic complexity distinguishes the human brain","volume":"29","author":"Oberheim","year":"2006","journal-title":"Trends Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.cell.2020.04.002","article-title":"Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program","volume":"181","author":"Geirsdottir","year":"2020","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"26173","DOI":"10.1073\/pnas.1902299116","article-title":"Cerebral cortical folding, parcellation, and connectivity in humans, nonhuman primates, and mice","volume":"116","author":"Donahue","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e23299","DOI":"10.1002\/ajp.23299","article-title":"Comparative neuropathology in aging primates: A perspective","volume":"83","author":"Edler","year":"2021","journal-title":"Am. J. Primatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1002\/ajp.22281","article-title":"Why primate models matter","volume":"76","author":"Phillips","year":"2014","journal-title":"Am. J. Primatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"102183","DOI":"10.1016\/j.pneurobio.2021.102183","article-title":"Modelling behaviors relevant to brain disorders in the nonhuman primate: Are we there yet?","volume":"208","author":"Scott","year":"2022","journal-title":"Prog. Neurobiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"26305","DOI":"10.1073\/pnas.1902293116","article-title":"The contribution of nonhuman primate research to the understanding of emotion and cognition and its clinical relevance","volume":"116","author":"Bernardi","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1007\/s12264-021-00732-6","article-title":"Co-editing PINK1 and DJ-1 Genes Via Adeno-Associated Virus-Delivered CRISPR\/Cas9 System in Adult Monkey Brain Elicits Classical Parkinsonian Phenotype","volume":"37","author":"Li","year":"2021","journal-title":"Neurosci. Bull."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"469","DOI":"10.24272\/j.issn.2095-8137.2021.023","article-title":"PINK1 gene mutation by pair truncated sgRNA\/Cas9-D10A in cynomolgus monkeys","volume":"42","author":"Chen","year":"2021","journal-title":"Zool. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1002\/alz.12318","article-title":"A novel tau-based rhesus monkey model of Alzheimer\u2019s pathogenesis","volume":"17","author":"Beckman","year":"2021","journal-title":"Alzheimer\u2019s Dement. J. Alzheimer\u2019s Assoc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/s41422-019-0142-y","article-title":"CRISPR\/Cas9-mediated PINK1 deletion leads to neurodegeneration in rhesus monkeys","volume":"29","author":"Yang","year":"2019","journal-title":"Cell Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/j.cell.2017.04.035","article-title":"Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys","volume":"169","author":"Chen","year":"2017","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1038\/cr.2016.93","article-title":"TALEN-based generation of a cynomolgus monkey disease model for human microcephaly","volume":"26","author":"Ke","year":"2016","journal-title":"Cell Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1093\/hmg\/ddu748","article-title":"Early Parkinson\u2019s disease symptoms in alpha-synuclein transgenic monkeys","volume":"24","author":"Niu","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1007\/s13238-020-00740-8","article-title":"Generation of a Hutchinson-Gilford progeria syndrome monkey model by base editing","volume":"11","author":"Wang","year":"2020","journal-title":"Protein Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"103207","DOI":"10.1016\/j.isci.2021.103207","article-title":"Synthetic amyloid-beta oligomers drive early pathological progression of Alzheimer\u2019s disease in nonhuman primates","volume":"24","author":"Yue","year":"2021","journal-title":"iScience"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1007\/s00401-019-01979-0","article-title":"Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains","volume":"137","author":"Yin","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/s41586-019-1278-0","article-title":"Atypical behaviour and connectivity in SHANK3-mutant macaques","volume":"570","author":"Zhou","year":"2019","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5492","DOI":"10.1002\/alz.14046","article-title":"Early blood immune molecular alterations in cynomolgus monkeys with a PSEN1 mutation causing familial Alzheimer\u2019s disease","volume":"20","author":"Li","year":"2024","journal-title":"Alzheimer\u2019s Dement. J. Alzheimer\u2019s Assoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/s41392-023-01601-6","article-title":"Tauopathy promotes spinal cord-dependent production of toxic amyloid-beta in transgenic monkeys","volume":"8","author":"Tu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/s41593-022-01251-x","article-title":"Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in a mouse model of Alzheimer\u2019s disease","volume":"26","author":"Zeng","year":"2023","journal-title":"Nat. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"113707","DOI":"10.1016\/j.expneurol.2021.113707","article-title":"Progressive parkinsonism due to mitochondrial impairment: Lessons from the MitoPark mouse model","volume":"341","author":"Beckstead","year":"2021","journal-title":"Exp. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.3233\/JAD-170045","article-title":"Mouse Models of Alzheimer\u2019s Disease","volume":"57","author":"Villegas","year":"2017","journal-title":"J. Alzheimer\u2019s Dis. JAD"},{"key":"ref_39","first-page":"5.67.1","article-title":"Rodent Models of Amyotrophic Lateral Sclerosis","volume":"69","author":"Philips","year":"2015","journal-title":"Curr. Protoc. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"nwaa292","DOI":"10.1093\/nsr\/nwaa292","article-title":"A cynomolgus monkey with naturally occurring Parkinson\u2019s disease","volume":"8","author":"Li","year":"2021","journal-title":"Natl. Sci. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e12284","DOI":"10.1002\/trc2.12284","article-title":"Early Alzheimer\u2019s disease-like reductions in gray matter and cognitive function with aging in nonhuman primates","volume":"8","author":"Frye","year":"2022","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e12289","DOI":"10.1002\/trc2.12289","article-title":"Characterization of cerebrospinal fluid biomarkers associated with neurodegenerative diseases in healthy cynomolgus and rhesus macaque monkeys","volume":"8","author":"Robertson","year":"2022","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"444","DOI":"10.24272\/j.issn.2095-8137.2020.088","article-title":"Age-associated changes in amyloid-beta and formaldehyde concentrations in cerebrospinal fluid of rhesus monkeys","volume":"41","author":"Li","year":"2020","journal-title":"Zool. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.jalz.2017.11.005","article-title":"The aged rhesus macaque manifests Braak stage III\/IV Alzheimer\u2019s-like pathology","volume":"14","author":"Paspalas","year":"2018","journal-title":"Alzheimer\u2019s Dement. J. Alzheimer\u2019s Assoc."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"957","DOI":"10.3233\/JAD-215303","article-title":"Characterization of Early Alzheimer\u2019s Disease-Like Pathological Alterations in Non-Human Primates with Aging: A Pilot Study","volume":"88","author":"Jester","year":"2022","journal-title":"J. Alzheimer\u2019s Dis. JAD"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/j.1750-3639.1991.tb00672.x","article-title":"Aged non-human primates: An animal model of age-associated neurodegenerative disease","volume":"1","author":"Price","year":"1991","journal-title":"Brain Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/s13578-021-00729-8","article-title":"Genetically modified large animal models for investigating neurodegenerative diseases","volume":"11","author":"Yang","year":"2021","journal-title":"Cell Biosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1007\/s13238-022-00912-8","article-title":"New pathogenic insights from large animal models of neurodegenerative diseases","volume":"13","author":"Yin","year":"2022","journal-title":"Protein Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.1016\/j.bbadis.2017.07.008","article-title":"Non-human primates as a model for aging","volume":"1864","author":"Colman","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13024-015-0031-x","article-title":"CRISPR\/Cas9: A powerful genetic engineering tool for establishing large animal models of neurodegenerative diseases","volume":"10","author":"Tu","year":"2015","journal-title":"Mol. Neurodegener."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/0304-3940(85)90223-X","article-title":"Co-culture study of rat neuron-glial interaction: Evidence of neuronal influence on myelination","volume":"59","author":"Fan","year":"1985","journal-title":"Neurosci. Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/s41580-024-00804-1","article-title":"Modelling human brain development and disease with organoids","volume":"26","author":"Birtele","year":"2025","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/S0166-2236(97)01122-3","article-title":"Organotypic slice cultures: A technique has come of age","volume":"20","author":"Gahwiler","year":"1997","journal-title":"Trends Neurosci."},{"key":"ref_54","first-page":"6","article-title":"Preparation and maintenance of organotypic slice cultures of CNS tissue","volume":"9","author":"Gahwiler","year":"2001","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1177\/026119290203000304","article-title":"Organotypic brain-slice cultures from adult rats: Approaches for a prolonged culture time","volume":"30","author":"Wilhelmi","year":"2002","journal-title":"Altern. Lab. Anim."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13024-019-0346-0","article-title":"Organotypic brain slice cultures to model neurodegenerative proteinopathies","volume":"14","author":"Croft","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_57","first-page":"1397","article-title":"Modeling alpha-Synucleinopathy in Organotypic Brain Slice Culture with Preformed alpha-Synuclein Amyloid Fibrils","volume":"10","author":"Roux","year":"2020","journal-title":"J. Park. Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"172","DOI":"10.2174\/1567205016666181212153138","article-title":"Organotypic Brain Slices of ADULT Transgenic Mice: A Tool to Study Alzheimer\u2019s Disease","volume":"16","author":"Humpel","year":"2019","journal-title":"Curr. Alzheimer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jneumeth.2018.05.021","article-title":"Free-floating adult human brain-derived slice cultures as a model to study the neuronal impact of Alzheimer\u2019s disease-associated Abeta oligomers","volume":"307","author":"Mendes","year":"2018","journal-title":"J. Neurosci. Methods"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"066026","DOI":"10.1088\/1741-2552\/aca261","article-title":"Revisiting the involvement of tau in complex neural network remodeling: Analysis of the extracellular neuronal activity in organotypic brain slice co-cultures","volume":"19","author":"Bouillet","year":"2022","journal-title":"J. Neural. Eng."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1084\/jem.20182184","article-title":"rAAV-based brain slice culture models of Alzheimer\u2019s and Parkinson\u2019s disease inclusion pathologies","volume":"216","author":"Croft","year":"2019","journal-title":"J. Exp. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1007\/s00401-020-02227-6","article-title":"Neuronal activity modulates alpha-synuclein aggregation and spreading in organotypic brain slice cultures and in vivo","volume":"140","author":"Wu","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s42003-019-0411-9","article-title":"Automated four-dimensional long term imaging enables single cell tracking within organotypic brain slices to study neurodevelopment and degeneration","volume":"2","author":"Linsley","year":"2019","journal-title":"Commun. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.pnpbp.2012.11.004","article-title":"Organotypic hippocampal slice culture from the adult mouse brain: A versatile tool for translational neuropsychopharmacology","volume":"41","author":"Kim","year":"2013","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"121340","DOI":"10.1016\/j.biomaterials.2021.121340","article-title":"Customized blood-brain barrier shuttle peptide to increase AAV9 vector crossing the BBB and augment transduction in the brain","volume":"281","author":"Zhang","year":"2022","journal-title":"Biomaterials"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.1016\/j.ymthe.2021.07.010","article-title":"A comprehensive study of a 29-capsid AAV library in a non-human primate central nervous system","volume":"29","author":"Kondratov","year":"2021","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"108914","DOI":"10.1016\/j.jneumeth.2020.108914","article-title":"Efficient whole brain transduction by systemic infusion of minimally purified AAV-PHP.eB","volume":"346","author":"Konno","year":"2020","journal-title":"J. Neurosci. Methods"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e59","DOI":"10.1002\/cpim.59","article-title":"Organotypic Brain Slice Cultures","volume":"123","author":"Humpel","year":"2018","journal-title":"Curr. Protoc. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"110055","DOI":"10.1016\/j.jneumeth.2023.110055","article-title":"Human organotypic brain slice cultures: A detailed and improved protocol for preparation and long-term maintenance","volume":"404","author":"Bak","year":"2024","journal-title":"J. Neurosci. Methods"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"311","DOI":"10.24272\/j.issn.2095-8137.2024.018","article-title":"A booming field of large animal model research","volume":"45","author":"Li","year":"2024","journal-title":"Zool. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.neuron.2023.01.016","article-title":"Neurodegeneration cell per cell","volume":"111","author":"Balusu","year":"2023","journal-title":"Neuron"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1515\/revneuro-2016-0035","article-title":"Protein misfolding and aggregation in neurodegenerative diseases: A review of pathogeneses, novel detection strategies, and potential therapeutics","volume":"30","author":"Gandhi","year":"2019","journal-title":"Rev. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/539179a","article-title":"Neurodegenerative diseases","volume":"539","author":"Heemels","year":"2016","journal-title":"Nature"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"4558","DOI":"10.1038\/s41380-025-03041-w","article-title":"Alzheimer\u2019s disease patient brain extracts induce multiple pathologies in novel vascularized neuroimmune organoids for disease modeling and drug discovery","volume":"30","author":"Ji","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e70828","DOI":"10.1002\/alz.70828","article-title":"Blood-based biomarkers for detecting Alzheimer\u2019s disease pathology in cognitively impaired individuals within specialized care settings: A systematic review and meta-analysis","volume":"21","author":"Pahlke","year":"2025","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e70648","DOI":"10.1002\/alz.70648","article-title":"Recent advances in neuroimaging of Alzheimer\u2019s disease and related dementias","volume":"21","author":"Ottoy","year":"2025","journal-title":"Alzheimers Dement."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"eadr8785","DOI":"10.1126\/science.adr8785","article-title":"Mapping early human blood cell differentiation using single-cell proteomics and transcriptomics","volume":"390","author":"Furtwangler","year":"2025","journal-title":"Science"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5100","DOI":"10.1016\/j.cell.2025.05.027","article-title":"STAMP: Single-cell transcriptomics analysis and multimodal profiling through imaging","volume":"188","author":"Pitino","year":"2025","journal-title":"Cell"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"eadz4351","DOI":"10.1126\/science.adz4351","article-title":"Autonomous biomedical research with an artificial intelligence agent","volume":"393","author":"Huang","year":"2026","journal-title":"Science"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/17\/1496\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:32:55Z","timestamp":1788496375000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/17\/1496"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,2]]},"references-count":79,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["biology15171496"],"URL":"https:\/\/doi.org\/10.3390\/biology15171496","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,2]]}}}