Taking aim at Alzheimer's disease through the mammalian target of rapamycin

Figures & data

Figure 1. mTOR signaling in Alzheimer's Disease. Activation of phosphoinositide 3-kinase (PI 3-K) following oxidative stress with mediators such as Aβ leads to phosphorylation and activation of protein kinase B (Akt). mTORC1 is composed of Raptor, the proline-rich Akt substrate 40 kDa (PRAS40), Deptor (DEP domain-containing mTOR interacting protein), and mLST8/GβL (mammalian lethal with Sec13 protein 8, termed mLST8). mTORC1 is more sensitive to the inhibitory effects of rapamycin than mTORC2. mTORC2 is composed of mLST8, Deptor, the mammalian stress-activated protein kinase interacting protein (mSIN1), and the protein observed with Rictor-1 (Protor-1). Akt can activate mTORC1 through phosphorylating TSC2 and disrupting the interaction between TSC2 and TSC1. TSC2 can function as a GTPase-activating protein (GAP) converting a small G protein Ras homologue enriched in brain (Rheb-GTP) to the inactive GDP-bound form (Rheb-GDP). AMPK phosphorylates TSC2 to lead to increased GAP activity to turn Rheb-GTP into Rheb-GDP and thus inhibits the activity of mTORC1. mTORC2 activates Akt to enhance cell survival and relies upon PKCα for cytoskeleton remodeling. mTORC2 also phosphorylates and activates SGK1 that can control ion transport. mTORC2 through Akt phosphorylates P-Rex1 and P-Rex2 to foster Rac activation and cell migration. mLST8 can promote mTOR kinase activity through p70 ribosomal S6 kinase (p70S6K) and the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4EBP1). Ultimately, apoptosis, autophagy, and necroptosis can be controlled by mTOR signaling such that during inhibition of mTOR with rapamycin, autophagy and necroptosis can be initiated. mTORC1 activation usually blocks apoptosis.

Table I. mTOR signaling in Alzheimer's disease (AD).

Target pathways	Biological outcome
Apoptosis	mTOR functions with multiple pathways that include PI 3-K, Akt, forkhead transcription factors, PRAS40, and p70S6K to prevent apoptotic cellular death in AD.
Autophagy	mTOR phosphorylates the mammalian homologue Atg13 and the mammalian Atg1 homologues ULK1 and ULK2 to block autophagy. In some models, mTOR inhibition that results in the induction of autophagy leads to improved cognitive function in animal models of AD. Yet, other models suggest that inflammatory stressors accompanied by autophagy activation may precipitate the pathology of AD.
Necroptosis	In animal models that exhibit components of AD, inhibitors of necroptosis prevent neuronal cell death and improve memory function, suggesting that necroptosis also contributes to AD pathology.
Memory formation	mTOR fosters dendritic protein synthesis in hippocampal neurons and is necessary for memory formation and consolidation. Reduction in mTOR signaling occurs in patients with AD. Loss of mTOR signaling in animal models of AD leads to impaired long-term potentiation and synaptic plasticity.
Neuronal injury	Loss of mTOR in conjunction with other pathways, such as RB1CC1, in AD patients leads to neuronal apoptosis and neuronal atrophy. Cellular protection against the toxicity of Aβ also may require mTOR modulation in conjunction with TSC2, PRAS40, BAD, and Bcl-xL.
Amyloid (Aβ)	Increased mTORC1 activity may be necessary to decrease BACE1 and reduce Aβ generation in AD. However, other studies suggest that inhibition of mTOR can enhance Aβ clearance in cell lines and animal models of AD. Repression of Aβ production also may require inhibition of Akt and mTOR with the concomitant activation of AMPK.