The silver lining of cerebrosterol in Alzheimer’s disease: the involvement of sirtuin 1 in neuroprotection.

Altered cholesterol metabolism in the brain is implicated both in the initiation and in the progression of Alzheimer’s disease (AD), and hypercholesterolemia is a potential risk factor. In particular, oxidized cholesterol, in the formof oxysterols, is believed to be one of the main triggers of AD. Oxysterols can accumulate in the brain, where they can behave as friends or foes: they cause neuron dysfunction and degeneration and contribute to neuroinflammation and amyloidogenesis, but they can also be neuroprotective. One of the main oxysterols most closely involved in AD pathogenesis is 24-hydroxycholesterol (24OH), also called cerebrosterol. The levels of 24OH are markedly reduced in the brain during AD progression, and it is likely that its reduction may accelerate the disease development, considering that it’s known from literature that 24OH may have neuroprotective effects. Moreover, the loss of 24OH proceeds in parallel with the reduction of sirtuin 1 (SIRT1), a deacetylase promoting neuroprotection. We demonstrated that 24OH activates the neuroprotective axis ROS/SIRT1/PGC1a in neuroblastoma cells, thus favoring Tau deacetylation and preventing Tau hyperphosphorylation. Thus, it would be clinically important to prevent the loss of 24OH in the brain, in order to stimulate long upon the expression of SIRT1 with the consequent delay of Tau pathology.