Divergent Metabolic Regulation of Autophagy and mTORC1—Early Events in Alzheimer’s Disease?

Abstract

Alzheimer’s disease (AD) is a progressive disease associated with the production and deposition of amyloid β-peptide (Aβ) aggregates and neurofibrillary tangles, which lead to synaptic and neuronal damage. Reduced autophagic flux has been widely associated with the accumulation of autophagic vacuoles (AV), which has been proposed to contribute to aggregate build-up observed in AD. As such, targeting autophagy regulation has received wide review, where an understanding as to how this mechanism can be controlled will be important to neuronal health. The mammalian target of rapamycin complex 1 (mTORC1), which was found to be hyperactive in AD brain, regulates autophagy and is considered to be mechanistically important to aberrant autophagy in AD. Hormones and nutrients such as insulin and leucine, respectively, positively regulate mTORC1 activation and are largely considered to inhibit autophagy. However, in AD brain there is a dysregulation of nutrient metabolism, linked to insulin resistance, where a role for insulin treatment to improve cognition has been proposed. Recent studies have highlighted that mitochondrial proteins such as glutamate dehydrogenase and the human branched chain aminotransferase protein, through metabolism of leucine and glutamate, differentially regulate mTORC1 and autophagy. As the levels of the hBCAT proteins are significantly increased in AD brain relative to aged-matched controls, we discuss how these metabolic pathways offer new potential therapeutic targets. In this review article, we highlight the core regulation of autophagy through mTORC1, focusing on how insulin and leucine will be important to consider in particular with respect to our understanding of nutrient load and AD pathogenesis.

Integrative functional analyses of the neurodegenerative disease-associated TECPR2 gene reveal its diverse roles

“…An energy balance is maintained between protein synthesis and autophagy, which are both coregulated by mTORC1 [64]. An imbalance between these processes is a hallmark of several diseases, including AD [13], HD [65] and various types of cancer [64]. Our analysis strongly supports the association of TECPR2 with these conditions (Fig.…”

“…We found that TECPR2 is tightly coexpressed with neurodevelopmental genes in a pattern that is consistent with a neurodevelopmental function. TECPR2 expression is also downregulated in postmortem prefrontal cortex from individuals with Alzheimer's disease (AD) and Huntington's disease (HD) as compared to matched controls, consistent with autophagy-related alterations seen in AD [13]. We further found that TECPR2 expression is tightly negatively correlated with that of ribosomal proteins, suggesting that TECPR2 might play a role in maintaining a balance between autophagy and protein synthesis.…”

Galantamine inhibits β‐amyloid‐induced cytostatic autophagy in PC12 cells through decreasing ROS production

“…However, it has been reported that excessive autophagy could result in autophagic cell death, suggesting that autophagy functions diversely in different conditions . Importantly, autophagy has been also purposed as a double‐edged sword in the pathogenesis of AD . On the one hand, the amyloid beta‐peptide (Aβ) aggregates were shown to be degraded by autophagy‐lysosome pathway as other ready‐to‐degrade cargo, and the secretion of Aβ can also be inhibited by the activation of autophagy .…”

LncRNA HULC mediates radioresistance via autophagy in prostate cancer cells

“…Phosphorylation of Thr119 of Beclin-1 causes dissociation of Bcl-2 from Beclin-1 resulting in autophagy activation ( 34 ). Autophagy is regulated by diverse pathways, including the mTOR cascade ( 35 ). In the present study, HULC interacted with Beclin-1 and its knockdown led to increase of Beclin-1 phosphorylation, along with inhibition of the mTOR pathway.…”