{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:33:21Z","timestamp":1768505601255,"version":"3.49.0"},"posted":{"date-parts":[[2023,1,5]]},"group-title":"Neuroscience","reference-count":68,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,7,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>People with early-onset Alzheimer\u2019s disease (AD) are at elevated seizure risk. Further, chronic seizures in pre-symptomatic stages may disrupt serotonin pathway-related protein expression, precipitating the onset of AD-related pathology and burden of neuropsychiatric comorbidities.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>2-3-month-old APP\/PS1, PSEN2-N141I, and transgenic control mice were sham or corneal kindled for 2 weeks to model chronic seizures. Seizure-induced changes in glia, serotonin pathway proteins, and amyloid \u03b2 levels in hippocampus and prefrontal cortex were quantified.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>APP\/PS1 mice experienced worsened mortality versus kindled Tg-controls. APP\/PS1 females were also more susceptible to chronic kindled seizures. These changes correlated with a marked downregulation of hippocampal tryptophan hydroxylase 2 and monoamine oxidase A protein expression compared to controls; these changes were not detected in PSEN2-N141I mice. Kindled APP\/PS1 mice exhibited amyloid \u03b2 overexpression and glial overactivity without plaque deposition. PSEN2 protein expression was AD model-dependent.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>Seizures evoked in pre-symptomatic APP\/PS1 mice promotes premature mortality in the absence of pathological A\u03b2 deposition. Disruptions in serotonin pathway metabolism are associated with increased glial reactivity and PSEN2 downregulation without amyloid \u03b2 deposition. This study provides the first direct evidence that seizures occurring prior to amyloid \u03b2 plaque accumulation worsen disease burden in an AD genotype-specific manner.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights:<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Seizures are a comorbidity in Alzheimer\u2019s disease that may worsen disease burden.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Pathological overlap between both neurological disorders is understudied.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Young APP\/PS1, but not PSEN2-N141I mice, have increased seizure-induced mortality.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Seizures reduce hippocampal serotonin pathway proteins only in young APP\/PS1 mice.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Kindled young APP\/PS1 mice have glial hyperactivity before amyloid \u03b2 accumulation.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2023.01.05.522897","type":"posted-content","created":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T23:20:12Z","timestamp":1672960812000},"source":"Crossref","is-referenced-by-count":2,"title":["Chronic evoked seizures in young pre-symptomatic APP\/PS1 mice induce serotonin changes and accelerate onset of Alzheimer\u2019s disease-related neuropathology"],"prefix":"10.64898","author":[{"given":"Aaron","family":"del Pozo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin M.","family":"Knox","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leanne M.","family":"Lehmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Davidson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seongheon Leo","family":"Rho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suman","family":"Jayadev","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa","family":"Barker-Haliski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"1","key":"2023080214102240000_2023.01.05.522897v2.1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s12974-020-01762-z","article-title":"Characterization of astrocytes throughout life in wildtype and APP\/PS1 mice after early-life stress exposure","volume":"17","year":"2020","journal-title":"J Neuroinflammation"},{"key":"2023080214102240000_2023.01.05.522897v2.2","doi-asserted-by":"crossref","unstructured":"Albertini, G. , D\u2019Andrea, I. , Druart, M. , Bechade, C. , Nieves-Rivera, N. , Etienne, F. , Le Magueresse, C. , Rebsam, A. , Heck, N. , Maroteaux, L. , & Roumier, A. 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