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Lithium has been suggested as a potential neuroprotective treatment, but the molecular mechanisms associated with its long-term effects are still not fully understood. In this study, we investigated the effects of chronic lithium treatment on hippocampal proteins associated with PI3K-related signaling in triple-transgenic Alzheimer\u2019s disease (3xTg-AD) mice. Wild-type and transgenic animals received either a lower or higher lithium dose for eight months. Hippocampal samples were analyzed by LC\u2013MS\/MS proteomics followed by protein interaction and functional enrichment analyses. From a total of 7768 identified proteins, bioinformatic analyses identified 157 proteins shared between APP-, MAPT-, and PI3K-associated datasets. Further network analyses identified 18 proteins related to PI3K signaling, including seven proteins shared among all three datasets: FKBP1A, HSPA1B, HSPA8, RAS-related proteins, RPL13, RPL19, and RPL24. These proteins are associated with protein folding, translation regulation, cellular stress responses, and signaling pathways. Chronic lithium treatment was associated with changes in the expression of these proteins in both wild-type and transgenic animals. The observed effects differed between the two lithium concentrations tested and did not follow a simple linear pattern. Our findings suggest that long-term lithium exposure is associated with changes in molecular networks related to proteostasis and translational regulation in the hippocampus. Although additional studies are needed to better understand the mechanisms involved, these results provide a proteomic framework for investigating lithium-sensitive pathways that may be relevant to Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1007\/s12035-026-06030-4","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T22:08:10Z","timestamp":1783375690000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chronic Lithium Exposure Reshapes PI3K\u2013mTOR-linked Proteostatic Networks in the Hippocampus of an Alzheimer\u2019s Disease Mouse Model"],"prefix":"10.1007","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5447-3880","authenticated-orcid":false,"given":"Ca\u00edque","family":"de Oliveira Portugal Couto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1546-7590","authenticated-orcid":false,"given":"Maria Luiza","family":"Hass das Eiras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2111-2018","authenticated-orcid":false,"given":"Jo\u00e3o Lucas","family":"Juliao de Morais","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4943-8949","authenticated-orcid":false,"given":"Carlos Wagner","family":"Leal Cordeiro J\u00fanior","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6962-5899","authenticated-orcid":false,"given":"Orestes Vicente","family":"Forlenza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2054-6356","authenticated-orcid":false,"given":"Vanessa","family":"de Jesus Rodrigues de Paula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"issue":"9","key":"6030_CR1","doi-asserted-by":"publisher","first-page":"2181","DOI":"10.7150\/IJBS.57078","volume":"17","author":"H Zhang","year":"2021","unstructured":"Zhang H, Wei W, Zhao M, Ma L, Jiang X, Pei H, Cao Y, Li H (2021) Interaction between A\u03b2 and tau in the pathogenesis of Alzheimer\u2019s disease. 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