{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T02:22:49Z","timestamp":1791685369355,"version":"4.3.4"},"reference-count":52,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,2,26]],"date-time":"2015-02-26T00:00:00Z","timestamp":1424908800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2015,6]]},"abstract":"Abstract<\/jats:title>The clinical symptoms of Alzheimer disease (AD<\/jats:styled-content>) include a gradual memory loss and subsequent dementia, and neuropathological deposition of senile plaques and neurofibrillary tangles. At the molecular level, AD<\/jats:styled-content> subjects present overt amyloid \u03b2 (A\u03b2) production and tau hyperphosphorylation. A\u03b2 species have been proposed to overactivate the phosphoinositide3\u2010kinase (PI<\/jats:styled-content>3K)\/Akt\/mammalian target of rapamycin (mTOR<\/jats:styled-content>) axis, which plays a central role in proteostasis. The current study investigated the status of the PI<\/jats:styled-content>3K\/Akt\/mTOR<\/jats:styled-content> pathway in post\u2010mortem tissue from the inferior parietal lobule (IPL<\/jats:styled-content>) at three different stages of AD<\/jats:styled-content>: late AD<\/jats:styled-content>, amnestic mild cognitive impairment (MCI<\/jats:styled-content>) and pre\u2010clinical AD<\/jats:styled-content> (PCAD<\/jats:styled-content>). Our findings suggest that the alteration of mTOR<\/jats:styled-content> signaling and autophagy occurs at early stages of AD<\/jats:styled-content>. We found a significant increase in A\u03b2 (1\u201342) levels, associated with reduction in autophagy (Beclin\u20101 and LC<\/jats:styled-content>\u20103) observed in PCAD<\/jats:styled-content>, MCI<\/jats:styled-content>, and AD<\/jats:styled-content> subjects. Related to the autophagy impairment, we found a hyperactivation of PI<\/jats:styled-content>3K\/Akt\/mTOR<\/jats:styled-content> pathway in IPL<\/jats:styled-content> of MCI<\/jats:styled-content> and AD<\/jats:styled-content> subjects, but not in PCAD<\/jats:styled-content>, along with a significant decrease in phosphatase and tensin homolog. An increase in two mTOR<\/jats:styled-content> downstream targets, p70S6K and 4EBP<\/jats:styled-content>1, occurred in AD<\/jats:styled-content> and MCI<\/jats:styled-content> subjects. Both AD<\/jats:styled-content> and MCI<\/jats:styled-content> subjects showed increased, insulin receptor substrate 1, a candidate biomarker of brain insulin resistance, and GSK<\/jats:styled-content>\u20103\u03b2, a kinase targeting tau phosphorylation. Nevertheless, tau phosphorylation was increased in the clinical groups. The results hint at a link between A\u03b2 and the PI<\/jats:styled-content>3K\/Akt\/mTOR<\/jats:styled-content> axis and provide further insights into the relationship between AD<\/jats:styled-content> pathology and insulin resistance. In addition, we speculate that the alteration of mTOR<\/jats:styled-content> signaling in the IPL<\/jats:styled-content> of AD<\/jats:styled-content> and MCI<\/jats:styled-content> subjects, but not in PCAD<\/jats:styled-content>, is due to the lack of substantial increase in oxidative stress.\nimage<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p>The figure represents the three different stages of Alzheimer Disease: Preclinical Alzheimer Disease (PCAD), Mild cognitive impairment (MCI) and late stage of Alzheimer Disease. The progression of the disease is associated with a reduction in autophagy (Beclin\u20101 and LC\u20103) observed in Inferior parietal lobe of PCAD, MCI, and AD subjects (light red). Related to the autophagy impairment, the graph shows the impairment of PI3K\/Akt\/mTOR in MCI and AD subjects (dark red).<\/jats:p>","DOI":"10.1111\/jnc.13037","type":"journal-article","created":{"date-parts":[[2015,1,27]],"date-time":"2015-01-27T12:56:34Z","timestamp":1422363394000},"page":"739-749","source":"Crossref","is-referenced-by-count":325,"title":["Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre\u2010clinical AD, amnestic mild cognitive impairment and late\u2010stage AD"],"prefix":"10.1111","volume":"133","author":[{"given":"Antonella","family":"Tramutola","sequence":"first","affiliation":[{"name":"Department of Biochemical Sciences Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy C.","family":"Triplett","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Kentucky Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Di Domenico","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana M.","family":"Niedowicz","sequence":"additional","affiliation":[{"name":"Sanders\u2010Brown Center on Aging University of Kentucky Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Sanders\u2010Brown Center on Aging University of Kentucky Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Coccia","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzia","family":"Perluigi","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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