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ORIGINAL RESEARCH article
Front. Cell. Neurosci.
Sec. Cellular Neuropathology
Volume 18 - 2024 |
doi: 10.3389/fncel.2024.1432359
This article is part of the Research Topic Metabolic Dysregulation in Neurodegenerative Diseases View all 4 articles
Dysregulated mTOR Networks in Experimental Sporadic Alzheimer's Disease
Provisionally accepted- 1 Rhode Island Hospital, Providence, Rhode Island, United States
- 2 Warren Alpert Medical School, Brown University, Providence, Rhode Island, United States
Background: Beyond the signature amyloid-beta plaques and neurofibrillary tangles, Alzheimer's 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. Objective: This study characterizes temporal lobe (TL) mTOR signaling abnormalities in a rat model of sporadic AD neurodegeneration. Methods: 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. Results: 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, AβPP, Aβ, AChE, 4-HNE, and GAPDH and reduced ubiquitin, IL-2, IL-6, and IFN-γ immunoreactivities. In addition, ic-STZ reduced TL pY1135/1136 -IGF-1R, Akt, PTEN, pS380 -PTEN, pS2448 -mTOR, p70S6K, pT412 -p70S6K, p/T-pT412 -p70S6K, p/T-Rictor, and p/T-Raptor. Conclusions: 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.
Keywords: Alzheimer's disease, mTOR, Streptozotocin, rat model, neurobehavior
Received: 13 May 2024; Accepted: 29 Aug 2024.
Copyright: © 2024 de la Monte and Tong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Suzanne M. de la Monte, Rhode Island Hospital, Providence, 02903, Rhode Island, United States
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