Differential Activation of mTOR Complex 1 Signaling in Human Brain with Mild to Severe Alzheimer's Disease

Abstract

Mammalian target of rapamycin (mTOR) signaling has been suggested to be effective in modifying cognitive status in animal models of Alzheimer's disease (AD), but little is known about its role in AD patients. We hereby tested whether mTOR signaling was activated and whether activated mTOR signaling was related to the degree of cognitive deficits in patients with AD. Autopsy brain hippocampal tissues were obtained from controls and patients with AD and Western blots were performed using antibodies against mTOR signaling molecules and RagC, an upstream component of mTOR complex 1 (mTORC1) signaling. We found that expression of mTOR/p-mTOR and its downstream targets S6/p-S6 and Raptor/p-Raptor were expressed in the control and AD hippocampus. The expression levels of these signaling molecules were significantly increased in the hippocampus at the severe stages of AD, compared to controls and other stages of AD. Interestingly, Rictor expression level was unaltered. In addition, RagC was increased in the hippocampus at the early, moderate, and severe stages of AD. Our data indicate that mTORC1, but not mTORC2, was activated in the AD brains and that the level of mTOR signaling activation was correlated with cognitive severity of AD patients.

Hippocampal Endosomal, Lysosomal, and Autophagic Dysregulation in Mild Cognitive Impairment

“…Unlike endosomal rabaptin5 and lysosomal Cat D, hippocampal levels of total mTOR and its active phosphorylated forms (pmTOR S2448 and pmTOR S2481) were not detectably altered in MCI or early AD. These results confirm and extend the observation that expression of mTOR and its active form pmTORs2448 in the hippocampus are stable early in the disease (present findings), whereas they are enhanced in advanced AD (33). Although the precise role of mTOR in AD pathology is still unknown, it has been reported that an increase in phosphorylated mTOR (s2481 and s2448) is associated with early tau phosphorylation in AD cortex (85, 86).…”

“…Reports suggest that the mammalian target of rapamycin (mTOR), a ubiquitous protein kinase, is important in autophagy regulation and tau phosphorylation (7, 32). Increased mTOR protein expression occurs in select neurons in severe AD (33), and inhibition of mTOR signaling induces autophagy, reduces tau and Aβ pathology and ameliorates behavioral deficits in young transgenic mice overexpressing Aβ and tau (34–37). The signaling adaptor protein, p62, which binds raptor, an integral component of the mTORC1 pathway and interacts with tumor necrosis factor receptor-associated factor 6 (traf6), is required for mTORC1 translocation to the lysosome and its subsequent activation (38).…”

Dual Targeting of mTOR Activity with Torin2 Potentiates Anticancer Effects of Cisplatin in Epithelial Ovarian Cancer

“…Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that controls cell survival and growth and is often found to be dysregulated in many diseases (6,7,8). mTOR functions by forming two different protein complexes; mTORC1 and mTORC2 (9).…”

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

“…The weight of evidence suggests that mTOR activity is increased in the temporal cortex and hippocampus of AD patients [295,296], and an activated but dysregulated Akt/ mTOR signalling pathway in the hippocampus would appear to be a universal feature of AD and MCI (reviewed by [297]). It is noteworthy that MTOR expression is normally increasingly inhibited in the ageing brain [298,299], and hence the existence of elevated mTOR activity in the hippocampus of AD patients could be a factor underpinning dysfunctional autophagic lysosomal clearance in that region of the brain, as discussed above.…”