Table 1.

The upstream and downstream components of mTOR signaling network associated with AD

Molecule involved	mTOR activity	Position in mTOR signaling	Proposed mechanism in AD	References
PI3-K/Akt	↓	Upstream of mTORC1 and downstream of mTORC2	The activation of PI3-K/Akt inhibits mTOR from enhancing autophagy and lysosomal degradation of Aβ, and limits the level of hyperphosphorylation of tau. Coupling of mTOR with PI3-K pathway by activated Akt regulates protein phosphatase 2A- and GSK-3-dependent phosphorylation of tau.	47,192,193
AMPK	↓	Upstream of mTORC1	AMPK targets mTOR to trigger autophagy and lysosomal degradation of Aβ. AMPK/mTOR signaling may improve insufficient energy metabolism and effect on amyloid plaque and neurofibrillary tangles via autophagy pathway.	47,132,198,199
MAPK	↑	Upstream of mTORC1	The interaction between mTOR and p38MAPK is a potent mediator in the pathogenesis of AD as a link between neuroinflammation, the formation of amyloid plaque, and the hyperphosphorylation of tau protein.	202,203
p53	↓	Upstream of mTORC1	p53, regulated by TSC2, is a molecular link between mTOR signaling pathways and RNA-activated protein kinase (PKR) as a center of cellular response to different stress signals and a critical target in AD.	185,186
GSK-3	↑	Upstream of mTORC1	GSK-3/mTOR signaling may be an effective actor in regulating the production of Aβ and hyperphosphorylation of tau.	32,83,114
LKB1	↓	Upstream of mTORC1	The LKB1/AMPK signaling negatively regulates mTOR signaling. LKB1/AMPK signaling pathway is associated with the pathogenesis of AD. The LKB1 complex in response to increase in the AMP/ATP ratio regulates Aβ generation and the aberrant phosphorylation of tau.	47,210,211
HER2	↑	Upstream of mTORC1	The activation of HER2 leads to Aβ production and the aberrant phosphorylation of tau by regulating MAPK, PI3K/Akt, PKC, and STAT signaling while these signaling pathways are all related to mTOR signaling.	216–219
IRS-1	↓	Upstream of mTORC1	IRS-1 has been implicated in Aβ generation and the aberrant phosphorylation of tau. The interaction between insulin/IRS-1 and mTOR is a critical regulator of Aβ generation and the aberrant phosphorylation of tau.	164,187,193,225
S6K/S6, p70S6K	↓	Downstream of mTORC1	The levels of total p70S6 kinase and p70S6 kinase phosphorylated at Thr421/Ser424 are correlated with the levels of tau. The level of ribosomal protein S6 is significantly increased in AD, while phosphorylated forms of mTOR and p70S6k are decreased in the cortex. p70S6K and S6 phosphorylate tau protein. The p70S6K can phosphorylate tau at S262, S214, and T212 sites, releasing tau from microtubules and resulting in microtubule disruption.	22,226,229,230,233
eIF2, eIF4E, 4EBP	↓	Downstream of mTORC1	mTOR activation stimulates translation initiation processes involving both 4EBP and p70S6 kinase/ribosomal S6 protein. The eIF2α levels were significantly increased in lymphocytes of AD patients and correlated with cognitive function. Phosphorylated 4EBP enhances total tau protein synthesis in the hippocampus. eIF4E phosphorylation is correlated with total- and hyperphosphorylated taus. The PKR/eIF2α pathway is responsible for the posttranscriptional increase in BACE1, which determines the Aβ pathogenesis.	19,185,235,237,240,241

Notes: ↓ means decreasing or decreased; ↑ means increasing or increased.

Abbreviations: AD, Alzheimer’s disease; Akt, protein kinase B; AMPK, AMP-activated protein kinase; 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; 4EBP, eIF4E/4E-binding protein; eIF2, eukaryotic Initiation Factor 2; eIF4E, eukaryotic translation initiation factor 4E; GSK-3, glycogen synthase kinase 3; HER2, human epidermal growth factor receptor-2; IRS-1, insulin receptor substrate-1; LKB1, liver kinase B 1; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PI3-K, phosphoinositide 3-kinase; PKC, protein kinase C; STAT, signal transducer and activator of transcription; TSC2, Tuberous Sclerosis Complex 2.