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
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