{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T05:12:18Z","timestamp":1792213938543,"version":"4.4.0"},"reference-count":47,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T00:00:00Z","timestamp":1677628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>A promising direction in the research on Alzheimer\u2019s Disease (AD) is the identification of biomarkers that better inform the disease progression of AD. However, the performance of amyloid-based biomarkers in predicting cognitive performance has been shown to be suboptimal. We hypothesise that neuronal loss could better inform cognitive impairment. We have utilised the 5xFAD transgenic mouse model that displays AD pathology at an early phase, already fully manifested after 6 months. We have evaluated the relationships between cognitive impairment, amyloid deposition, and neuronal loss in the hippocampus in both male and female mice. We observed the onset of disease characterized by the emergence of cognitive impairment in 6-month-old 5xFAD mice coinciding with the emergence of neuronal loss in the subiculum, but not amyloid pathology. We also showed that female mice exhibited significantly increased amyloid deposition in the hippocampus and entorhinal cortex, highlighting sex-related differences in the amyloid pathology of this model. Therefore, parameters based on neuronal loss might more accurately reflect disease onset and progression compared to amyloid-based biomarkers in AD patients. Moreover, sex-related differences should be considered in studies involving 5xFAD mouse models.<\/jats:p>","DOI":"10.3390\/cells12050780","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T03:54:56Z","timestamp":1677729296000},"page":"780","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Sex Differences between Neuronal Loss and the Early Onset of Amyloid Deposits and Behavioral Consequences in 5xFAD Transgenic Mouse as a Model for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7275-0351","authenticated-orcid":false,"given":"Chi Him","family":"Poon","sequence":"first","affiliation":[{"name":"Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"San Tung Nicholas","family":"Wong","sequence":"additional","affiliation":[{"name":"Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8934-738X","authenticated-orcid":false,"given":"Jaydeep","family":"Roy","sequence":"additional","affiliation":[{"name":"Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingyi","family":"Wang","sequence":"additional","affiliation":[{"name":"Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3170-9891","authenticated-orcid":false,"given":"Hui Wang Hujo","family":"Chan","sequence":"additional","affiliation":[{"name":"Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7667-0604","authenticated-orcid":false,"given":"Harry","family":"Steinbusch","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6211 LK Maastricht, The Netherlands"},{"name":"Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute Science and Technology (DGIST), Daegu 42988, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan","family":"Blokland","sequence":"additional","affiliation":[{"name":"Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, 6211 LK Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasin","family":"Temel","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6211 LK Maastricht, The Netherlands"},{"name":"Department of Neurosurgery, Maastricht University Medical Centre, Maastricht University, 6211 LK Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Aquili","sequence":"additional","affiliation":[{"name":"Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"},{"name":"College of Health and Education, Discipline of Psychology, Murdoch University, Perth 6150, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6692-6285","authenticated-orcid":false,"given":"Lee Wei","family":"Lim","sequence":"additional","affiliation":[{"name":"Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/nrd3505","article-title":"The amyloid cascade hypothesis for Alzheimer\u2019s disease: An appraisal for the development of therapeutics","volume":"10","author":"Karran","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15056","DOI":"10.1038\/nrdp.2015.56","article-title":"Alzheimer\u2019s disease","volume":"1","author":"Masters","year":"2015","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer\u2019s disease: The amyloid cascade hypothesis","volume":"256","author":"Hardy","year":"1992","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"100005","DOI":"10.1016\/j.bionps.2019.100005","article-title":"Diagnostic biomarkers of Alzheimer\u2019s disease: A state-of-the-art review","volume":"1","author":"Khoury","year":"2019","journal-title":"Biomark. Neuropsychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1212\/01.WNL.0000063311.58879.01","article-title":"Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer\u2019s disease","volume":"60","author":"Giannakopoulos","year":"2003","journal-title":"Neurology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.nicl.2013.02.006","article-title":"Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer\u2019s disease","volume":"2","author":"Chetelat","year":"2013","journal-title":"Neuroimage Clin"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/j.neurobiolaging.2009.04.002","article-title":"Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease","volume":"30","author":"Price","year":"2009","journal-title":"Neurobiol. Aging"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10129","DOI":"10.1523\/JNEUROSCI.1202-06.2006","article-title":"Intraneuronal \u03b2-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer\u2019s Disease Mutations: Potential Factors in Amyloid Plaque Formation","volume":"26","author":"Oakley","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s13024-017-0231-7","article-title":"Practical considerations for choosing a mouse model of Alzheimer\u2019s disease","volume":"12","author":"Jankowsky","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/s41582-018-0032-9","article-title":"Sex differences in Alzheimer disease\u2013the gateway to precision medicine","volume":"14","author":"Ferretti","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1006\/smns.1994.1039","article-title":"Regional neuronal loss in aging and Alzheimer\u2019s disease: A brief review","volume":"6","author":"Coleman","year":"1994","journal-title":"Semin. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1750-1326-10-1","article-title":"Abeta reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level","volume":"10","author":"Sadleir","year":"2015","journal-title":"Mol. Neurodegener."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bhattacharya, S., Haertel, C., Maelicke, A., and Montag, D. (2014). Galantamine slows down plaque formation and behavioral decline in the 5XFAD mouse model of Alzheimer\u2019s disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089454"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1750-1326-8-2","article-title":"Neuron loss in the 5XFAD mouse model of Alzheimer\u2019s disease correlates with intraneuronal A\u03b242 accumulation and Caspase-3 activation","volume":"8","author":"Eimer","year":"2013","journal-title":"Mol. Neurodegener."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"196.e29","DOI":"10.1016\/j.neurobiolaging.2010.05.027","article-title":"Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Abeta aggregation in the 5XFAD mouse model of Alzheimer\u2019s disease","volume":"33","author":"Jawhar","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s13020-021-00546-8","article-title":"Neurogenesis-dependent antidepressant-like activity of Hericium erinaceus in an animal model of depression","volume":"16","author":"Chong","year":"2021","journal-title":"Chin. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"37568","DOI":"10.1038\/srep37568","article-title":"Tetratricopeptide repeat domain 9A modulates anxiety-like behavior in female mice","volume":"6","author":"Lim","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wolf, A., Bauer, B., Abner, E.L., Ashkenazy-Frolinger, T., and Hartz, A.M. (2016). A Comprehensive Behavioral Test Battery to Assess Learning and Memory in 129S6\/Tg2576 Mice. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0147733"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"964336","DOI":"10.3389\/fnagi.2022.964336","article-title":"Distribution and inter-regional relationship of amyloid-beta plaque deposition in a 5xFAD mouse model of Alzheimer\u2019s disease","volume":"14","author":"Tsui","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1111\/nyas.14850","article-title":"Transcorneal electrical stimulation enhances cognitive functions in aged and 5XFAD mouse models","volume":"1515","author":"Yu","year":"2022","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"112","DOI":"10.14336\/AD.2022.0706","article-title":"Prelimbic Cortical Stimulation with L-methionine Enhances Cognition through Hippocampal DNA Methylation and Neuroplasticity Mechanisms","volume":"14","author":"Poon","year":"2023","journal-title":"Aging Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.jneumeth.2009.07.010","article-title":"Improved method for combination of immunocytochemistry and Nissl staining","volume":"184","author":"Wittmann","year":"2009","journal-title":"J. Neurosci. Methods"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.14336\/AD.2019.1026","article-title":"Rodent Models of Amyloid-Beta Feature of Alzheimer\u2019s Disease: Development and Potential Treatment Implications","volume":"11","author":"Poon","year":"2020","journal-title":"Aging Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1101\/lm.1094208","article-title":"Spatial memory in the Morris water maze and activation of cyclic AMP response element-binding (CREB) protein within the mouse hippocampus","volume":"15","author":"Porte","year":"2008","journal-title":"Learn. Mem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14731","DOI":"10.1073\/pnas.97.26.14731","article-title":"Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin(1A) receptors","volume":"97","author":"Sarnyai","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1038\/s41467-019-09118-9","article-title":"Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer\u2019s disease model","volume":"10","author":"Zhong","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1007\/s12035-016-9802-9","article-title":"Curcumin Ameliorates Memory Decline via Inhibiting BACE1 Expression and beta-Amyloid Pathology in 5xFAD Transgenic Mice","volume":"54","author":"Zheng","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7967","DOI":"10.1038\/ncomms8967","article-title":"Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer\u2019s disease pathology","volume":"6","author":"Baruch","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2220","DOI":"10.4103\/0366-6999.162507","article-title":"Reduction of Glucose Metabolism in Olfactory Bulb is an Earlier Alzheimer\u2019s Disease-related Biomarker in 5XFAD Mice","volume":"128","author":"Xiao","year":"2015","journal-title":"Chin. Med. J. (Engl.)"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1021\/acschemneuro.6b00278","article-title":"Disease-Modifying Effects of M1 Muscarinic Acetylcholine Receptor Activation in an Alzheimer\u2019s Disease Mouse Model","volume":"8","author":"Lebois","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/s41398-018-0201-z","article-title":"Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer\u2019s disease","volume":"8","author":"Okamoto","year":"2018","journal-title":"Transl. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.jneumeth.2015.07.022","article-title":"Comparison of unbiased estimation of neuronal number in the rat hippocampus with different staining methods","volume":"254","author":"Zhu","year":"2015","journal-title":"J. Neurosci. Methods"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.tins.2010.05.004","article-title":"\u2018Too much good news\u2019\u2013are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer\u2019s disease?","volume":"33","author":"Zahs","year":"2010","journal-title":"Trends Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e284","DOI":"10.1038\/tp.2013.59","article-title":"Mechanisms that lessen benefits of beta-secretase reduction in a mouse model of Alzheimer\u2019s disease","volume":"3","author":"Devi","year":"2013","journal-title":"Transl. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s13195-017-0297-z","article-title":"Alzheimer\u2019s disease prevention: From risk factors to early intervention","volume":"9","author":"Minguillon","year":"2017","journal-title":"Alzheimers Res. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1177\/0023677216653984","article-title":"Does age matter? The impact of rodent age on study outcomes","volume":"51","author":"Jackson","year":"2017","journal-title":"Lab. Anim."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2019). 2019 Alzheimer\u2019s disease facts and figures. Alzheimers Dement., 15, 321\u2013387.","DOI":"10.1016\/j.jalz.2019.01.010"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41597-021-01054-y","article-title":"Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer\u2019s disease","volume":"8","author":"Forner","year":"2021","journal-title":"Sci. Data"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5669","DOI":"10.1038\/s41380-020-0701-0","article-title":"Chronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer\u2019s disease mouse model","volume":"26","author":"Ng","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1002\/cne.24551","article-title":"Sex-biased hippocampal pathology in the 5XFAD mouse model of Alzheimer\u2019s disease: A multi-omic analysis","volume":"527","author":"Bundy","year":"2019","journal-title":"J. Comp. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.3233\/JAD-180678","article-title":"5xFAD Mice Display Sex-Dependent Inflammatory Gene Induction During the Prodromal Stage of Alzheimer\u2019s Disease","volume":"70","author":"Manji","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/330658a0","article-title":"Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve","volume":"330","author":"Lindholm","year":"1987","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1007\/s00401-018-1881-4","article-title":"Sex-specific genetic predictors of Alzheimer\u2019s disease biomarkers","volume":"136","author":"Deming","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/78682","article-title":"Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease","volume":"6","author":"Bard","year":"2000","journal-title":"Nat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/s41593-019-0560-7","article-title":"Microglial microRNAs mediate sex-specific responses to tau pathology","volume":"23","author":"Kodama","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1007\/s11055-017-0427-x","article-title":"Mechanisms of Neuron Loss in Alzheimer\u2019s Disease","volume":"47","author":"Mukhin","year":"2017","journal-title":"Neurosci. Behav. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.neuroscience.2015.08.037","article-title":"Effects of BACE1 haploinsufficiency on APP processing and Abeta concentrations in male and female 5XFAD Alzheimer mice at different disease stages","volume":"307","author":"Devi","year":"2015","journal-title":"Neuroscience"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/5\/780\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:45:08Z","timestamp":1760121908000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/5\/780"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,1]]},"references-count":47,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["cells12050780"],"URL":"https:\/\/doi.org\/10.3390\/cells12050780","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,1]]}}}