Neuron survival modulated by 24-hydroxycholesterol: the role of sirtuin pathway in Alzheimer's Disease.

Alzheimer’s disease (AD) is a devastating neurodegenerative condition typified by the pathological accumulation of amyloid β peptides and neurofibrillary tangles of hyperphosphorylated Tau protein within the brain. Moreover, Tau acetylation is abnormally high in the brains of AD patients, even in the early stage of the disease. Excessive Tau acetylation prevents ubiquitin-mediated proteolysis of phospho-Tau, favoring its accumulation and aggregation. A vicious circle has been found to connect oxidative stress and inflammation in AD, but also altered cholesterol metabolism significantly contribute to neuronal damage. In this connection, considerable evidence indicates that oxidized cholesterol is the driving force behind the development of AD. The oxysterols most widely considered to be potentially implicated in the pathogenesis of AD are 24- and 27-hydroxycholesterol (24OH and 27OH), both of enzymatic origin. In addition, other oxysterols have been found in AD brain deriving from cholesterol autoxidation, including 7-ketocholesterol (7K). To date, the conversion of cholesterol into 24OH, unlike other oxysterols, has been considered to potentially exert a protective action on the brain, although the available results are still contradictory. Aims. We aimed to study the possible effect of 24OH on neurotoxic phospho-Tau accumulation, in comparison to 7K, by modulating the neuroprotective Sirtuin 1 (SIRT1) pathway in SK-N-BE cells. Furthermore we aimed to correlate these findings with oxysterol and SIRT1 levels in the brain of AD patients. Results. We observed that 24OH, unlike 7K, reduces Tau phosphorylation. This peculiar behavior of 24OH depends on the enhancement of ROS generation and the consequent SIRT1 upregulation. SIRT1 deacetylates PGC-1 and Tau leading to the beneficial reduction of Tau phosphorylation and aggregation, thus favoring neuron survival. In parallel, an ex vivo study was carried out on autopsy samples of frontal and occipital cortex from human AD (early and late AD) and normal brains: 24-hydroxylase expression and the levels of its product 24OH were significantly decreased in late AD; conversely, the levels of 7K were significantly increased with the severity of the disease. During AD progression it has been also demonstrated SIRT1 lowering, in agreement with neurofibrillary tangles accumulation, and the consequent upregulation of some proinflammatory molecules.