Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Jun:169:382-396.
doi: 10.1016/j.freeradbiomed.2021.04.025. Epub 2021 Apr 30.

mTOR in Alzheimer disease and its earlier stages: Links to oxidative damage in the progression of this dementing disorder

M Perluigi  1 , F Di Domenico  1 , E Barone  1 , D A Butterfield  2
Affiliations
Review

mTOR in Alzheimer disease and its earlier stages: Links to oxidative damage in the progression of this dementing disorder

M Perluigi et al. Free Radic Biol Med. 2021 Jun.

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population and has worldwide impact. The etiology of the disease is complex and results from the confluence of multiple mechanisms ultimately leading to neuronal loss and cognitive decline. Among risk factors, aging is the most relevant and accounts for several pathogenic events that contribute to disease-specific toxic mechanisms. Accumulating evidence linked the alterations of the mammalian target of rapamycin (mTOR), a serine/threonine protein kinase playing a key role in the regulation of protein synthesis and degradation, to age-dependent cognitive decline and pathogenesis of AD. To date, growing studies demonstrated that aberrant mTOR signaling in the brain affects several pathways involved in energy metabolism, cell growth, mitochondrial function and proteostasis. Recent advances associated alterations of the mTOR pathway with the increased oxidative stress. Disruption of all these events strongly contribute to age-related cognitive decline including AD. The current review discusses the main regulatory roles of mTOR signaling network in the brain, focusing on its role in autophagy, oxidative stress and energy metabolism. Collectively, experimental data suggest that targeting mTOR in the CNS can be a valuable strategy to prevent/slow the progression of AD.

Keywords: Alzheimer's disease; Oxidative stress; Protein aggregation; Proteostasis; mTOR.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
In physiological conditions (depicted in the upper part of the figure), several oxidant stimuli, such as low levels of free radicals (ROS) and low amount of amyloid beta peptide (Aß), lead to coordinated stress responses (UPR, UPS and autophagy) for the removal of damaged molecules/organelles. In pathological conditions (depicted in the lower part of the figure), the overproduction of oxidants overwhelms the protein quality control, in part due to the oxidation/inactivation of some of its members, resulting in the accumulation of oxidized/dysfunctional proteins that are harmful for neuronal survival. In this scenario, mTOR hyperactivation, as it occurs in AD brain, not only contributes to impair autophagy machinery, but also dysregulates insulin signaling (by feedback mechanisms).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, Skipper L, Murphy MP, Beard J, Das P, Jansen K, DeLucia M, Lin WL, Dolios G, Wang R, Eckman CB, Dickson DW, Hutton M, Hardy J, Golde T, Abeta42 is essential for parenchymal and vascular amyloid deposition in mice, Neuron 47(2) (2005) 191–199. - PMC - PubMed
    1. O’Brien RJ, Wong PC, Amyloid precursor protein processing and Alzheimer’s disease, Annu Rev Neurosci 34 (2011) 185–204. - PMC - PubMed
    1. Hayden EY, Teplow DB, Amyloid beta-protein oligomers and Alzheimer’s disease, Alzheimers Res Ther 5(6) (2013) 60. - PMC - PubMed
    1. Selkoe DJ, Hardy J, The amyloid hypothesis of Alzheimer’s disease at 25 years, EMBO Mol Med 8(6) (2016) 595–608. - PMC - PubMed
    1. Iqbal K, Liu F, Gong CX, Grundke-Iqbal I, Tau in Alzheimer disease and related tauopathies, Curr Alzheimer Res 7(8) (2010) 656–64. - PMC - PubMed

Publication types

Substances