Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre‐clinical AD, amnestic mild cognitive impairment and late‐stage AD

Abstract

The clinical symptoms of Alzheimer disease (AD) include a gradual memory loss and subsequent dementia, and neuropathological deposition of senile plaques and neurofibrillary tangles. At the molecular level, AD subjects present overt amyloid b (Ab) production and tau hyperphosphorylation. Ab species have been proposed to overactivate the phosphoinositide3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) axis, which plays a central role in proteostasis. The current study investigated the status of the PI3K/Akt/mTOR pathway in post-mortem tissue from the inferior parietal lobule (IPL) at three different stages of AD: late AD, amnestic mild cognitive impairment (MCI) and pre-clinical AD (PCAD). Our findings suggest that the alteration of mTOR signaling and autophagy occurs at early stages of AD. We found a significant increase in Ab (1-42) levels, associated with reduction in autophagy (Beclin-1 and LC-3) observed in PCAD, MCI, and AD subjects. Related to the autophagy impairment, we found a hyperactivation of PI3K/ Akt/mTOR pathway in IPL of MCI and AD subjects, but not in PCAD, along with a significant decrease in phosphatase and tensin homolog. An increase in two mTOR downstream targets, p70S6K and 4EBP1, occurred in AD and MCI subjects. Both AD and MCI subjects showed increased, insulin receptor substrate 1, a candidate biomarker of brain insulin resistance, and GSK-3b, a kinase targeting tau phosphorylation. Nevertheless, tau phosphorylation was increased in the clinical groups. The results hint at a link between Ab and the PI3K/Akt/mTOR axis and provide further insights into the relationship between AD pathology and insulin resistance. In addition, we speculate that the alteration of mTOR signaling in the IPL of AD and MCI subjects, but not in PCAD, is due to the lack of substantial increase in oxidative stress.

Increased Mammalian Target of Rapamycin Signaling Contributes to the Accumulation of Protein Oxidative Damage in a Mouse Model of Down's Syndrome

“…AD and DS neuropathology are characterized by increased OS and the concomitant impairment of the mTOR/autophagy axis [5,31]. In particular, DS patients demonstrated the early mTOR hyperactivation within the brain coupled with the impairment of autophagy, insulin cascade and increased amyloid-β load suggesting that all these events could trigger the appearance of AD symptoms in DS [21,32].…”

Molecular network of neuronal autophagy in the pathophysiology and treatment of depression

“…In the meantime, mTORC1 inhibits autophagy, an essential protein-degradation and recycling system [52] ; for example, PI3K-Akt-mTOR is associated with autophagy impairment and is impaired in mild cognitive impairment and AD [53] . mTOR regulates both neuroprotective (via autophagy) and neuroregenerative (via protein synthesis) functions in various diseases of the central nervous system [42] .…”

Nutritional supplementations and administration considerations for sarcopenia in older adults

“…Maintaining and controlling protein synthesis are the primary roles of mTORC1, whereas the role of mTORC2 is less clearly perceived [45]. While activation of mTORC1 will further phosphorylates/activates p70 ribosomal S6 protein kinase (p70S6K) and protein synthesis, its inhibition activates autophagy machinery to eliminate damaged components and save energy for stressful conditions [46]. Thus, due to the central role of mTOR in several signaling pathways, it is implicated in the pathogenesis of diseases in which growth and homeostasis are compromised, e.g.…”