Neurons and Exercise

Neurons and Exercise

Monday, October 11, 2021

mTOR is higher than normal in Alzheimer’s disease (AD) brains making it a risk factor for AD

 

mTOR Activity Increases in AD Brains Due to Inhibition of PP2A by Aluminum

Dennis N. Crouse

mTOR Complex 1 (mTORC1) includes mTOR a serine/threonine kinase that is found in all eukaryotic cells, phosphorylates several targets, and acts as a master regulator of protein synthesis and degradation. The activity of mTOR is higher than normal in Alzheimer’s disease (AD) brains making it a risk factor for AD that is independent of the ApoE status of patients. (Yates 2013) mTOR activation is a biomarker of autoimmune disorders, cancer, obesity, aging, and possibly AD. (Perl 2015) The activation of mTOR results in an AD associated increase in phosphorylation of both mTOR and downstream targets of mTOR in neurons of AD brains:

·         mTOR phosphorylated at Ser2481 (3-fold higher than normal) and Ser2448 (2.6-fold higher in those with AD than normal) (Pei 2008,  Li 2005, Griffin 2005)

·         p70S6K, a downstream target of mTOR, phosphorylated at Thr421 and Ser424 (phosphorylation is 4-fold higher in those with AD than normal) (An 2003)

·         eIF4E eukaryotic translation factor 4E a downstream target of mTOR 28 (eIF4E’s phosphorylation level is 100-fold higher in those with AD than normal) (Li 2004)

The phosphorylated forms of mTOR and p70S6K may represent putative indicators of cognitive impairments in AD. (Pei 2008) This higher mTOR activity is likely due to higher-than-normal phosphorylation of mTOR at Ser2481 and Ser2448. (Li 2005, Griffin 2005) Also, higher-than-normal levels of phosphorylation of p70S6K and eIF4E were significantly increased in AD brains and correlated with Baark’s stage and the levels of p-tau a biomarker of AD. (An 2003, Li 2004) Also, levels of phosphorylated p70S6K are higher in neurons that later develop NFTs a biomarker of AD. (An 2003)

The enzyme PP2A lowers the phosphorylation level of the mTORC1 complex and by doing so suppresses activity of mTORC1 complex. (Apostolidis 2016) However, aluminum inhibits PP2A in the AD brain thereby preventing suppression of mTORC1 and increasing the activity of the mTORC1 complex. (Yamamoto 1990)  Therefore, aluminum, a biomarker of AD, inhibits PP2A causing both increased mTORC1 activity and increased risk of AD. Facilitating aluminum excretion by drinking OSA rich water will likely allow PP2A to suppress mTORC1 activity and decreased the risk of AD.

Sirolimus (a.k.a. rapamycin) is a macrolide that both lowers mTORC1’s activity and inhibits cell proliferation and growth by interaction with FK506-binding protein. Sirolimus functions as an immunosuppressant and is used to prevent organ transplant rejection by inhibiting the activation of T-cells and B-cells required  by the immune system. (Mukherjee 2009) Taking sirolimus can lower the bodies resistance to bacterial and viral infection, such as COVID-19. Sirolimus can also cause lung toxicity as interstitial pneumonitis. (Chhajed 2006) Therefore, drinking OSA rich water to facilitate the elimination of aluminum and lower mTOR activity is safer than taking sirolimus.

References

An, W.-L., et al.; Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer’s disease; Am. J. Pathol.; Aug.; 163(2):591-607 (2003)

Chhajed, P.N., et al.; Patterns of pulmonary complications associated with sirolimus; Respriation; 73:367-74 (2006)

Griffin, R.J., et al.; Acrivation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer’s disease pathology; J. Neurochem. 93:105-17 (2005) 

Li, X., et al.; Phosphorylated eukaryotic translation factor 4E is elevated in Alzheimer brain; Neuroreport; Oct.; 15(14):2237-40 (2004) 

Li, X., et al.; Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer’s disease brain; FEBS J.; 272:4211-20 (2005)

Mukherjee, S., and Mukherjee, U.; A comprehensive review of immunosuppression used for liver transplantation; J. Transplantation; Article ID 701464 p1-20 (2009)

Pei, J.-J., and Hugon, J.; mTOR-dependent signalling in Alzheimer’s disease; J. Cell. Mol. Med.; 12(6B):2525-32 (2008)

Perl, A.; mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging; Ann. N. Y. Acad. Sci.; June; 1346(1):33-44 (2015)

Yamamoto, H., et al.; Dephosphorylation of tau factor by protein phosphatase 2A in synaptosomal cytosol fractions, and inhibition by aluminum; J. Neuroscience; 55:683-90 (1990)

Yates, S.C., et al.; Dysfunction of the mTOR pathway is a risk factor for Alzheimer’s disease; Acta Neuropath. Comm.; 1:3 (2013)