Alzheimer's disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid β (Aβ) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis. Herein, we review recent progress with respect to Aβ-and tau-associated mechanisms, and discuss glial dysfunction in AD with emphasis on neuronal and glial receptors that mediate Aβ-induced toxicity. We also discuss other critical factors that may affect AD pathogenesis, including genetics, aging, variables related to environment, lifestyle habits, and describe the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota. Although we have gained much towards understanding various aspects underlying this devastating neurodegenerative disorder, greater commitment towards research in molecular mechanism, diagnostics and treatment will be needed in future AD research.

AKT activation requires phosphorylation of the activation loop (T308) by 3-phosphoinositide-dependent protein kinase 1 (PDK1) and the hydrophobic motif (S473) by the mammalian target of rapamycin complex 2 (mTORC2). We recently observed that phosphorylation of the AKT hydrophobic motif was dramatically elevated, rather than decreased, in mTOR knockout heart tissues, indicating the existence of other kinase(s) contributing to AKT phosphorylation. Here we show that the atypical IκB kinase ε and TANK-binding kinase 1 (IKKε/TBK1) phosphorylate AKT on both the hydrophobic motif and the activation loop in a manner dependent on PI3K signaling. This dual phosphorylation results in a robust AKT activation in vitro. Consistently, we found that growth factors can induce AKT (S473) phosphorylation in Rictor −/− cells, and this effect is insensitive to mTOR inhibitor Torin1. In IKKε/TBK1 double-knockout cells, AKT activation by growth factors is compromised. We also observed that TBK1 expression is elevated in the mTOR knockout heart tissues, and that TBK1 is required for Ras-induced mouse embryonic fibroblast transformation. Our observations suggest a physiological function of IKKε/TBK1 in AKT regulation and a possible mechanism of IKKε/TBK1 in oncogenesis by activating AKT.IKK-related protein kinase | protein kinase B | cancer T he AKT protein kinase is a major signaling hub and a key downstream effector of the PI3K pathway (1, 2). AKT plays a major role in cell growth, proliferation, and survival (3). Under physiological conditions, AKT activity is intricately controlled, whereas pathological AKT activation contributes to human cancers (4, 5). On PI3K activation, AKT is recruited to plasma membrane via its PH domain, which is critical for AKT phosphorylation (6, 7). Phosphorylation of the activation loop T308 by 3-phosphoinositide-dependent protein kinase 1 (PDK1) is essential for AKT activation (8). However, full AKT activation also requires phosphorylation of the regulatory hydrophobic motif S473 by mTORC2, which consists of mTOR, Rictor, Sin1, and mLST8 subunits (9-12). AKT (S473) phosphorylation is defective in Rictor or mSin1 knockout cells, demonstrating the importance of mTORC2 in AKT (S473) phosphorylation (10,13,14). DNA-PK also has been implicated in AKT hydrophobic motif phosphorylation in response to DNA double-strand breaks (15, 16).Accumulating evidence indicates an mTOR-independent kinase responsible for AKT (S473) phosphorylation. Two studies using tissue-specific knockout mice indicated that mTOR is not required for AKT hydrophobic motif phosphorylation in skeletal and cardiac muscles (17, 18). We found that ablation of mTOR in heart cardiac muscles indeed decreased phosphorylation of the mTORC1 substrate S6K, but AKT (S473) phosphorylation was dramatically increased in these mice. Consistent with our observation, mTOR or Raptor/Rictor double-knockout in skeletal muscle also increases AKT (S473) phosphorylation (17)(18)(19). Collectively, these data provide compelling evidence for the existence of other A...

Mechanistic target of rapamycin (MTOR) plays a critical role in the regulation of cell growth and in the response to energy state changes. Drugs inhibiting MTOR are increasingly used in antineoplastic therapies. Myocardial MTOR activity changes during hypertrophy and heart failure (HF). However, whether MTOR exerts a positive or a negative effect on myocardial function remains to be fully elucidated. Here, we show that ablation of Mtor in the adult mouse myocardium results in a fatal, dilated cardiomyopathy that is characterized by apoptosis, autophagy, altered mitochondrial structure, and accumulation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). 4E-BP1 is an MTOR-containing multiprotein complex-1 (MTORC1) substrate that inhibits translation initiation. When subjected to pressure overload, Mtor-ablated mice demonstrated an impaired hypertrophic response and accelerated HF progression. When the gene encoding 4E-BP1 was ablated together with Mtor, marked improvements were observed in apoptosis, heart function, and survival. Our results demonstrate a role for the MTORC1 signaling network in the myocardial response to stress. In particular, they highlight the role of 4E-BP1 in regulating cardiomyocyte viability and in HF. Because the effects of reduced MTOR activity were mediated through increased 4E-BP1 inhibitory activity, blunting this mechanism may represent a novel therapeutic strategy for improving cardiac function in clinical HF.

In Figure 3E, the units provided for carbohydrate oxidation and fat oxidation were incorrect. The units for both should be g/d/kg 0.75 .The authors regret the error.

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