Entorhinal cholecystokinin in Alzheimer’s disease: its earliest vulnerability and rescue effects across different disease stages

Entorhinal cholecystokinin in Alzheimer’s disease: its earliest vulnerability and rescue effects across different disease stages | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Entorhinal cholecystokinin in Alzheimer’s disease: its earliest vulnerability and rescue effects across different disease stages Yixuan Sui, Nan Zhang, Xi Chen, Micky D Tortorella, Jufang He This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7630814/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Feb, 2026 Read the published version in Cellular and Molecular Neurobiology → Version 1 posted 13 You are reading this latest preprint version Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. The entorhinal cortex (Ent) is among the earliest affected regions, and its neuropeptide cholecystokinin (CCK) supports neocortical-associated memory. Although our previous work demonstrated that CCK treatment rescues cognition and neuroplasticity in aged AD mice, the correlations among CCK expression, synaptic function, and cognitive decline with aging remain poorly understood. Using 3xTg-AD mice (2–18 months), we performed stereological, histological, and molecular analyses to evaluate brain atrophy, neuronal loss, glial responses, and gene expression. Cognitive function was assessed using novel object recognition and rotarod tests, while synaptic integrity was measured via electrophysiological recordings. Importantly, we investigated the therapeutic potential of CCK-B receptor (CCK-BR) agonists on cognition and neuroplasticity across disease stages of AD. The Ent exhibits significant atrophy and excitatory neuronal loss as early as 7 months of age, confirming its role as one of the earliest and most severely affected regions in AD. CCK was downregulated earlier than other synaptic genes in the Ent and other brain regions. CCK-4 treatment rescued deficits in synaptic plasticity and cognition in 3xTg-AD mice across multiple disease stages. Long-term administration of HT-267, an optimized CCK-4 analogue, in young 3xTg-AD mice delayed cognitive decline, enhanced synaptic scaffolding, and restored long-term potentiation in both the cortex and hippocampus (HPC). Our findings identify CCK downregulation as an early biomarker in AD and demonstrate the therapeutic effects of CCK-BR agonists in mitigating cognitive and synaptic deficits from mild to severe disease stages. The ability of long-term CCK-4 analogue treatment to decelerate AD progression indicates its promise as an early intervention strategy. Alzheimer’s disease Entorhinal cortex Cholecystokinin Drug development Learning and memory Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterial.docx StatisticalMethodsData.xlsx Rawdata.xlsx OnlineAbstractFigure.png Graphical abstract Our findings identify CCK downregulation as an early biomarker in AD and demonstrate the therapeutic effects of CCK-BR agonists on cognitive and synaptic deficits across mild to severe AD stages. Long-term treatment of CCK-4 analogue decelerates AD progression, indicating its promising potential for early intervention in AD. Cite Share Download PDF Status: Published Journal Publication published 14 Feb, 2026 Read the published version in Cellular and Molecular Neurobiology → Version 1 posted Editorial decision: Revision requested 13 Nov, 2025 Reviews received at journal 10 Nov, 2025 Reviews received at journal 07 Nov, 2025 Reviews received at journal 03 Nov, 2025 Reviews received at journal 28 Oct, 2025 Reviewers agreed at journal 20 Oct, 2025 Reviewers agreed at journal 16 Oct, 2025 Reviewers agreed at journal 16 Oct, 2025 Reviewers agreed at journal 16 Oct, 2025 Reviewers invited by journal 15 Oct, 2025 Editor assigned by journal 14 Oct, 2025 Submission checks completed at journal 14 Oct, 2025 First submitted to journal 13 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7630814","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":536446606,"identity":"e85a379a-7c12-4131-8793-f59612b12bba","order_by":0,"name":"Yixuan Sui","email":"","orcid":"","institution":"City University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Yixuan","middleName":"","lastName":"Sui","suffix":""},{"id":536446607,"identity":"bb79eb36-37ba-496e-be6a-02ae3af7492c","order_by":1,"name":"Nan 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17:05:46","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":218859,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraphical abstract\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur findings identify CCK downregulation as an early biomarker in AD and demonstrate the therapeutic effects of CCK-BR agonists on cognitive and synaptic deficits across mild to severe AD stages. Long-term treatment of CCK-4 analogue decelerates AD progression, indicating its promising potential for early intervention in AD.\u003c/p\u003e","description":"","filename":"OnlineAbstractFigure.png","url":"https://assets-eu.researchsquare.com/files/rs-7630814/v1/b5b0f5cb06928fe7b5c93e84.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Entorhinal cholecystokinin in Alzheimer’s disease: its earliest vulnerability and rescue effects across different disease stages","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cellular-and-molecular-neurobiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cemn","sideBox":"Learn more about [Cellular and Molecular Neurobiology](https://www.springer.com/journal/10571)","snPcode":"10571","submissionUrl":"https://submission.nature.com/new-submission/10571/3","title":"Cellular and Molecular Neurobiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Alzheimer’s disease, Entorhinal cortex, Cholecystokinin, Drug development, Learning and memory","lastPublishedDoi":"10.21203/rs.3.rs-7630814/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7630814/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAlzheimer\u0026rsquo;s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. The entorhinal cortex (Ent) is among the earliest affected regions, and its neuropeptide cholecystokinin (CCK) supports neocortical-associated memory. Although our previous work demonstrated that CCK treatment rescues cognition and neuroplasticity in aged AD mice, the correlations among CCK expression, synaptic function, and cognitive decline with aging remain poorly understood.\u003c/p\u003e\u003cp\u003eUsing 3xTg-AD mice (2\u0026ndash;18 months), we performed stereological, histological, and molecular analyses to evaluate brain atrophy, neuronal loss, glial responses, and gene expression. Cognitive function was assessed using novel object recognition and rotarod tests, while synaptic integrity was measured via electrophysiological recordings. Importantly, we investigated the therapeutic potential of CCK-B receptor (CCK-BR) agonists on cognition and neuroplasticity across disease stages of AD.\u003c/p\u003e\u003cp\u003eThe Ent exhibits significant atrophy and excitatory neuronal loss as early as 7 months of age, confirming its role as one of the earliest and most severely affected regions in AD. CCK was downregulated earlier than other synaptic genes in the Ent and other brain regions. CCK-4 treatment rescued deficits in synaptic plasticity and cognition in 3xTg-AD mice across multiple disease stages. Long-term administration of HT-267, an optimized CCK-4 analogue, in young 3xTg-AD mice delayed cognitive decline, enhanced synaptic scaffolding, and restored long-term potentiation in both the cortex and hippocampus (HPC).\u003c/p\u003e\u003cp\u003eOur findings identify CCK downregulation as an early biomarker in AD and demonstrate the therapeutic effects of CCK-BR agonists in mitigating cognitive and synaptic deficits from mild to severe disease stages. The ability of long-term CCK-4 analogue treatment to decelerate AD progression indicates its promise as an early intervention strategy.\u003c/p\u003e","manuscriptTitle":"Entorhinal cholecystokinin in Alzheimer’s disease: its earliest vulnerability and rescue effects across different disease stages","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-29 17:05:41","doi":"10.21203/rs.3.rs-7630814/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-13T08:46:11+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-11T02:10:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-07T16:21:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-03T13:31:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-28T17:28:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"292439756528674718898100361716561949704","date":"2025-10-20T20:41:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"90519346395843593902141457173201100781","date":"2025-10-16T14:24:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"215695895418166721520446596380641757997","date":"2025-10-16T08:42:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"332680011923705447287783325889432759412","date":"2025-10-16T06:48:01+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-15T09:27:27+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-14T14:36:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-14T10:19:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cellular and Molecular Neurobiology","date":"2025-10-13T15:30:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cellular-and-molecular-neurobiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cemn","sideBox":"Learn more about [Cellular and Molecular Neurobiology](https://www.springer.com/journal/10571)","snPcode":"10571","submissionUrl":"https://submission.nature.com/new-submission/10571/3","title":"Cellular and Molecular Neurobiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"34bb3ade-49d7-4b2c-b5fa-f568193164ec","owner":[],"postedDate":"October 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-16T16:06:23+00:00","versionOfRecord":{"articleIdentity":"rs-7630814","link":"https://doi.org/10.1007/s10571-026-01689-8","journal":{"identity":"cellular-and-molecular-neurobiology","isVorOnly":false,"title":"Cellular and Molecular Neurobiology"},"publishedOn":"2026-02-14 15:59:01","publishedOnDateReadable":"February 14th, 2026"},"versionCreatedAt":"2025-10-29 17:05:41","video":"","vorDoi":"10.1007/s10571-026-01689-8","vorDoiUrl":"https://doi.org/10.1007/s10571-026-01689-8","workflowStages":[]},"version":"v1","identity":"rs-7630814","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7630814","identity":"rs-7630814","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}