{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T01:38:44Z","timestamp":1790213924155,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"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 of China","doi-asserted-by":"publisher","award":["2022YFC3600201"],"award-info":[{"award-number":["2022YFC3600201"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Synaptic plasticity impairment and behavioral deficits constitute classical pathological hallmarks in early-stage Alzheimer\u2019s disease (AD). Emerging evidence suggests these synaptic dysfunctions may stem from metabolic dysregulation, particularly impaired aerobic glycolysis. As a key product of astrocyte-mediated aerobic glycolysis, lactate serves dual roles as both an energy substrate and a signaling molecule, playing a critical regulatory role in synaptic plasticity and long-term memory formation. This study investigated whether exogenous L-lactate supplementation could ameliorate synaptic dysfunction and cognitive deficits in early-stage AD models. Our findings reveal significant reductions in hippocampal lactate levels in experimental AD mice. Systemic administration of L-lactate (200 mg\/kg) effectively restored physiological lactate concentrations in both hippocampal tissue and cerebrospinal fluid (CSF). Chronic L-lactate treatment significantly improved spatial learning and memory performance in behavioral assessments. Electrophysiological recordings demonstrated that either acute bath application of L-lactate (2 mM) to hippocampal slices or chronic intraperitoneal administration enhanced high-frequency stimulation (HFS)-induced long-term potentiation (LTP) magnitude in 3xTg-AD mice. Ultrastructural analysis revealed that L-lactate treatment enhanced synaptic density and improved morphological features of hippocampal synapses. At the molecular level, L-lactate administration upregulated synaptic marker synaptophysin (SYP) expression while downregulating activity-regulated cytoskeletal-associated protein (ARC) levels in AD mice. These multimodal findings demonstrate that exogenous L-lactate supplementation effectively restores synaptic plasticity and cognitive function in early-stage 3xTg-AD mice through concurrent improvements at behavioral, structural, and molecular levels.<\/jats:p>","DOI":"10.3390\/ijms26041486","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T05:34:32Z","timestamp":1739252072000},"page":"1486","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["L-Lactate Administration Improved Synaptic Plasticity and Cognition in Early 3xTg-AD Mice"],"prefix":"10.3390","volume":"26","author":[{"given":"Yaxin","family":"Wang","sequence":"first","affiliation":[{"name":"School of Physical Education, Shanxi University, Taiyuan 030006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Physical Education, Shanxi University, Taiyuan 030006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kerrigan, T.L., and Randall, A.D. 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