{"paper_id":"1649325b-41a9-45b5-935d-cccdad89e585","body_text":"Loss of newborn neuron function accelerates neuroinflammation and amyloid accumulation via dentate gyrus circuit alteration in a mouse model of Alzheimer’s disease | 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 Loss of newborn neuron function accelerates neuroinflammation and amyloid accumulation via dentate gyrus circuit alteration in a mouse model of Alzheimer’s disease Risako Tamura, Riki Kawabata, Chenxu Lei, Haowei Li, Daiki Hayashi, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9168444/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Chronic neuroinflammation, characterized by persistent activation of microglia and astrocytes, is now recognized not merely as a bystander but as a fundamental driver of Alzheimer’s disease (AD) pathogenesis. Importantly, neuroinflammatory processes have been reported to be associated with disruptions in excitation–inhibition balance and network instability. Adult hippocampal newborn neurons play an important role in maintaining dentate gyrus (DG) circuit stability, and alterations in this neural population are among the earliest signs of AD pathology. We previously developed a conditional mouse model (NBN–TeTX) that selectively lose the function of hippocampal newborn neurons and demonstrated that these neurons are essential for maintaining hippocampal network balance. These observations raise the possibility that loss of newborn neuron function may contribute to neuroinflammatory responses through disruption of the DG circuit in AD pathology. Methods To investigate the impact of loss of newborn neuron function on neuroinflammation in AD model mice, we generated NBN-APP mice by crossing NBN-TeTX mice with APPswe/PS1dE9 (APP) mice. We performed snRNA-seq to characterize the transcriptomic landscape of the DG. Amyloid β (Aβ) deposition and glial morphological changes were assessed by histological analysis. Hippocampus-dependent cognitive function was evaluated using the Morris water maze and contextual fear conditioning tests. Results NBN-APP mice exhibited increased Aβ accumulation in the molecular layer of the DG compared with APP mice. Transcriptional analysis of the DG revealed an excitatory transcriptional signature in granule cells, together with increased disease-associated astrocytic signature ( p = 3.08 × 10 ⁻11 ) indicative of enhanced neuroinflammation in NBN-APP mice. Histological analyses confirmed increased abundance of astrocytes in the hippocampus, together with elevated levels of pro-inflammatory cytokines, including TNF-α and IL-6. These alterations were associated with impairments in hippocampus-dependent cognitive function. Conclusion Our findings suggest that loss of hippocampal newborn neuron function in an AD mouse model may disrupt DG circuit balance, contributing to increased neuronal excitability and astrocyte reactivation. Increased abundance of reactive astrocytes was accompanied by enhanced neuroinflammatory responses in the hippocampus. These changes were associated with increased Aβ accumulation and cognitive impairment. Thus, impaired newborn neuron function may act as an upstream trigger of neuroinflammatory processes in AD, rather than merely representing a downstream consequence of disease progression. adult hippocampal neurogenesis Alzheimer’s disease neuroinflammation microglia Amyloid β dentate gyrus local circuit dentate gyrus Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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-9168444\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":612334560,\"identity\":\"5102b46f-6c5b-4193-ad82-16b70b4c7231\",\"order_by\":0,\"name\":\"Risako Tamura\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Risako\",\"middleName\":\"\",\"lastName\":\"Tamura\",\"suffix\":\"\"},{\"id\":612334561,\"identity\":\"8ca27322-64e4-432b-86a2-5cc97d56db1c\",\"order_by\":1,\"name\":\"Riki Kawabata\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Riki\",\"middleName\":\"\",\"lastName\":\"Kawabata\",\"suffix\":\"\"},{\"id\":612334564,\"identity\":\"8e1c3579-be95-46d3-986e-ce3d1a503da7\",\"order_by\":2,\"name\":\"Chenxu Lei\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Chenxu\",\"middleName\":\"\",\"lastName\":\"Lei\",\"suffix\":\"\"},{\"id\":612334565,\"identity\":\"4e32e5f9-8126-4302-ba03-ee46575e2e05\",\"order_by\":3,\"name\":\"Haowei Li\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Haowei\",\"middleName\":\"\",\"lastName\":\"Li\",\"suffix\":\"\"},{\"id\":612334567,\"identity\":\"a2613ce4-cb6f-48c1-ae5a-79e4292d5eec\",\"order_by\":4,\"name\":\"Daiki 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Importantly, neuroinflammatory processes have been reported to be associated with disruptions in excitation\\u0026ndash;inhibition balance and network instability. Adult hippocampal newborn neurons play an important role in maintaining dentate gyrus (DG) circuit stability, and alterations in this neural population are among the earliest signs of AD pathology. We previously developed a conditional mouse model (NBN\\u0026ndash;TeTX) that selectively lose the function of hippocampal newborn neurons and demonstrated that these neurons are essential for maintaining hippocampal network balance. These observations raise the possibility that loss of newborn neuron function may contribute to neuroinflammatory responses through disruption of the DG circuit in AD pathology.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e \\u003cp\\u003eTo investigate the impact of loss of newborn neuron function on neuroinflammation in AD model mice, we generated NBN-APP mice by crossing NBN-TeTX mice with APPswe/PS1dE9 (APP) mice. We performed snRNA-seq to characterize the transcriptomic landscape of the DG. Amyloid β (Aβ) deposition and glial morphological changes were assessed by histological analysis. Hippocampus-dependent cognitive function was evaluated using the Morris water maze and contextual fear conditioning tests.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e \\u003cp\\u003eNBN-APP mice exhibited increased Aβ accumulation in the molecular layer of the DG compared with APP mice. Transcriptional analysis of the DG revealed an excitatory transcriptional signature in granule cells, together with increased disease-associated astrocytic signature (\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;3.08 \\u0026times; 10\\u003csup\\u003e⁻11\\u003c/sup\\u003e) indicative of enhanced neuroinflammation in NBN-APP mice. Histological analyses confirmed increased abundance of astrocytes in the hippocampus, together with elevated levels of pro-inflammatory cytokines, including TNF-α and IL-6. These alterations were associated with impairments in hippocampus-dependent cognitive function.\\u003c/p\\u003e\\u003ch2\\u003eConclusion\\u003c/h2\\u003e \\u003cp\\u003eOur findings suggest that loss of hippocampal newborn neuron function in an AD mouse model may disrupt DG circuit balance, contributing to increased neuronal excitability and astrocyte reactivation. Increased abundance of reactive astrocytes was accompanied by enhanced neuroinflammatory responses in the hippocampus. These changes were associated with increased Aβ accumulation and cognitive impairment. 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