In recent years, it has become clear that cholesterol dysmetabolism in the brain is involved in Alzheimer’s disease (AD) development: it is now believed that cholesterol oxidation products, known as oxysterols, are the link connecting altered brain cholesterol metabolism to AD. Previously, we observed that the cerebrosterol 24-hydroxycholesterol (24-OHC) reduces the accumulation of phosphorylated tau protein up-regulating the neuroprotective deacetylase sirtuin 1 (SIRT1) in human neuroblastoma SK-N-BE cells. We are now investigating how the 24-OHC might modulate tau levels. We have shown that 24-OHC, through the activation of the axis SIRT1/PGC1/Nrf2, promotes tau deacetylation and ubiquitination, key events leading to tau proteasomal degradation, with the consequent decrease of both phosphorylated and total tau levels. We have demonstrated that 24-OHC, via SIRT-1/PGC1 activation, induces a significant up-regulation of both Nrf2 expression and synthesis. Moreover, 24-OHC leads to a decrease of Nrf2/Keap1 complex inducing a nuclear translocation of Nrf2, with the consequent increase of transcription levels of antioxidant proteins (i.e. HO-1, NQO1) able to counteract oxidative stress. In conclusion, the administration of 24-OHC, as Nrf2 activator, may provide a therapeutic strategy aimed at reducing tau accumulation and oxidative damage, both promising targets in AD prevention.

24-hydroxycholesterol as Nrf2 activator able to enhance tau clearance for treatment of Alzheimer’s disease

Testa G.;Giannelli S.;Gamba P.;Staurenghi E.;Sottero B.;Poli G.;Leonarduzzi G.
2019

Abstract

In recent years, it has become clear that cholesterol dysmetabolism in the brain is involved in Alzheimer’s disease (AD) development: it is now believed that cholesterol oxidation products, known as oxysterols, are the link connecting altered brain cholesterol metabolism to AD. Previously, we observed that the cerebrosterol 24-hydroxycholesterol (24-OHC) reduces the accumulation of phosphorylated tau protein up-regulating the neuroprotective deacetylase sirtuin 1 (SIRT1) in human neuroblastoma SK-N-BE cells. We are now investigating how the 24-OHC might modulate tau levels. We have shown that 24-OHC, through the activation of the axis SIRT1/PGC1/Nrf2, promotes tau deacetylation and ubiquitination, key events leading to tau proteasomal degradation, with the consequent decrease of both phosphorylated and total tau levels. We have demonstrated that 24-OHC, via SIRT-1/PGC1 activation, induces a significant up-regulation of both Nrf2 expression and synthesis. Moreover, 24-OHC leads to a decrease of Nrf2/Keap1 complex inducing a nuclear translocation of Nrf2, with the consequent increase of transcription levels of antioxidant proteins (i.e. HO-1, NQO1) able to counteract oxidative stress. In conclusion, the administration of 24-OHC, as Nrf2 activator, may provide a therapeutic strategy aimed at reducing tau accumulation and oxidative damage, both promising targets in AD prevention.
Annual Meeting of the Society-for-Free-Radical-Research- Europe (SFRRE) on Redox Homeostasis - From Signaling to Damage
Ferrara
19-21 Giugno, 2019
139
S53
S53
Testa G., Giannelli S., Gamba P., Staurenghi E., Sottero B., Poli G., Leonarduzzi G.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1718074
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