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Cell. Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Beyond the signature amyloid-beta plaques and neurofibrillary tangles, Alzheimer\u2019s disease (AD) has been shown to exhibit dysregulated metabolic signaling through insulin and insulin-like growth factor (IGF) networks that crosstalk with the mechanistic target of rapamycin (mTOR). Its broad impact on brain structure and function suggests that mTOR is likely an important therapeutic target for AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study characterizes temporal lobe (TL) mTOR signaling abnormalities in a rat model of sporadic AD neurodegeneration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Long Evans rats were given intracerebroventricular injections of streptozotocin (ic-STZ) or saline (control), and 4 weeks later, they were administered neurobehavioral tests followed by terminal harvesting of the TLs for histopathological study and measurement of AD biomarkers, neuroinflammatory\/oxidative stress markers, and total and phosphorylated insulin\/IGF-1-Akt-mTOR pathway signaling molecules.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Rats treated with ic-STZ exhibited significantly impaired performance on Rotarod (RR) and Morris Water Maze (MWM) tests, brain atrophy, TL and hippocampal neuronal and white matter degeneration, and elevated TL pTau, A\u03b2PP, A\u03b2, AChE, 4-HNE, and GAPDH and reduced ubiquitin, IL-2, IL-6, and IFN-\u03b3 immunoreactivities. In addition, ic-STZ reduced TL<jats:sup>pY1135\/1136<\/jats:sup>-IGF-1R, Akt, PTEN,<jats:sup>pS380<\/jats:sup>-PTEN,<jats:sup>pS2448<\/jats:sup>-mTOR, p70S6K,<jats:sup>pT412<\/jats:sup>-p70S6K, p\/T-<jats:sup>pT412<\/jats:sup>-p70S6K, p\/T-Rictor, and p\/T-Raptor.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Experimental ic-STZ-induced sporadic AD-type neurodegeneration with neurobehavioral dysfunctions associated with inhibition of mTOR signaling networks linked to energy metabolism, plasticity, and white matter integrity.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fncel.2024.1432359","type":"journal-article","created":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T10:46:59Z","timestamp":1727261219000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Dysregulated mTOR networks in experimental sporadic Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"18","author":[{"given":"Suzanne M.","family":"de la Monte","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,25]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1074\/jbc.M101521200","article-title":"Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action.","volume":"277","author":"Aguirre","year":"2002","journal-title":"J. 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