Naturally Secreted Amyloid-β Increases Mammalian Target of Rapamycin (mTOR) Activity via a PRAS40-mediated Mechanism

Abstract

Reducing the mammalian target of rapamycin (mTOR) activity increases lifespan and health span in a variety of organisms. Alterations in protein homeostasis and mTOR activity and signaling have been reported in several neurodegenerative disorders, including Alzheimer disease (AD); however, the causes of such deregulations remain elusive. Here, we show that mTOR activity and signaling are increased in cell lines stably transfected with mutant amyloid precursor protein (APP) and in brains of 3xTg-AD mice, an animal model of AD. In addition, we show that in the 3xTg-AD mice, mTOR activity can be reduced to wild type levels by genetically preventing A␤ accumulation. Similarly, intrahippocampal injections of an anti-A␤ antibody reduced A␤ levels and normalized mTOR activity, indicating that high A␤ levels are necessary for mTOR hyperactivity in 3xTg-AD mice. We also show that the intrahippocampal injection of naturally secreted A␤ is sufficient to increase mTOR signaling in the brains of wild type mice. The mechanism behind the A␤-induced mTOR hyperactivity is mediated by the proline-rich Akt substrate 40 (PRAS40) as we show that the activation of PRAS40 plays a key role in the A␤-induced mTOR hyperactivity. Taken together, our data show that A␤ accumulation, which has been suggested to be the culprit of AD pathogenesis, causes mTOR hyperactivity by regulating PRAS40 phosphorylation. These data further indicate that the mTOR pathway is one of the pathways by which A␤ exerts its toxicity and further support the idea that reducing mTOR signaling in AD may be a valid therapeutic approach.Amyloid plaques and neurofibrillary tangles are hallmark neuropathological lesions of Alzheimer disease (AD), 3 the most common form of neurodegenerative disorder (1). Neurofibrillary tangles are intracellular inclusions formed of hyperphosphorylated Tau (2-4). Plaques are extracellular inclusions mainly formed of a small peptide called amyloid-␤ (A␤) (5, 6). Clinically, AD is characterized by profound memory loss and cognitive dysfunction (7). Growing evidence is converging on soluble A␤ as a mediator of early cognitive decline in AD (8, 9). Although the molecular mechanisms underlying A␤-induced cognitive decline remain elusive, soluble A␤ oligomers have been shown to alter signal transduction pathways that are key for learning and memory, suggesting that alterations in such pathways may underlie the onset of cognitive decline in AD (10).The mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that forms two multiprotein complexes known as mTOR complex (mTORC) 1 and 2 (11). mTORC1 controls protein homeostasis; its activity is inhibited by rapamycin, and it contains mTOR, raptor, proline-rich Akt substrate 40 kDa (PRAS40), and mLT8. mTORC2, which is insensitive to rapamycin, controls cellular shape by modulating actin function and contains mTOR, rictor, mLST8, and hSIN (11, 12). In mTORC1, raptor binds to mTOR substrates and is necessary for mTOR activity (13). PRAS40 is another mTOR regulatory protein, which inhibits mTOR...

Amyloid Precursor Protein (APP) Affects Global Protein Synthesis in Dividing Human Cells

“…Evidence suggesting that APP operates independently of mTORC‐1 are as follows: (i) APP downregulation did not modify the phosphorylation state of p70S6 kinase or its downstream target S6; (ii) APP depletion did not yield any modification in the mTOR/RAPTOR ratio; (iii) APP depletion had no effect on Akt phosphorylation at either T308 or S473; and (iv) we failed to find any association of APP to mTORC‐1 complexes (not shown). In support of previous studies (Caccamo et al, 2011), we found that APP depletion caused a modest increase of PRAS40 phosphorylation. PRAS40 has been proposed as an mTORC‐1 inhibitor, which, upon Akt phosphorylation at T246, activates mTORC‐1 (Sancak et al, 2007).…”

“…A recent study suggested that the APP fragment Aβ stimulates mTORC‐1 activity via PRAS40 phosphorylation (Caccamo et al, 2011). We observed a modest increase in PRAS40 phosphorylation upon APP depletion (Supplementary Fig.…”

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…Moreover, the insufficient autophagy could also lower the clearance of misfolded tau proteins, leading to the accumulation of tau aggregates in the cytoplasm of neurons (Li et al., 2017). On the contrary, Aβ could also elevate mTOR activity through PRAS40 (proline‐rich Akt substrate 40 kDa)‐mediated mechanism and thus further dampens the autophagic response (Caccamo, Maldonado, Majumder, Medina, & Holbein, 2011). On the other hand, the autophagy‐independent pathway is also a vital mechanism that triggers both pathological formation of Aβ plaques and tau aggregates.…”

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

“…Rapamycin, an mTOR dependent inducer of autophagy, has been shown to up-regulate autophagy, reducing aberrant protein aggregation in ALS (Sarkar et al, 2008;Harrison et al, 2009;Malagelada et al, 2010;Dehay et al, 2010;Caccamo et al, 2011;Hetz et al, 2009). However, rapamycin was demonstrated to worsen motor neuron loss and to reduce the survival of SOD1 G93A mice when administrated in advanced stages of the disease, while at early stages it may exert positive effects .…”