Oxysterols along the course of Alzheimer’s disease.

Introduction Alzheimer’s disease (AD) is associated with neuroinflammation, oxidative stress and dysregulated lipid homeostasis within the brain. The molecular mechanisms underlying this disease are not clear, and till date no biomarkers for AD early diagnosis are available. Oxysterols could represent new biomarkers for AD since their levels change in the brains during AD progression. In particular, oxysterols deriving from cholesterol oxidation by CYP46A1 and CYP27A1, respectively 24-hydroxycholesterol and 27-hydroxycholesterol, and oxysterols deriving from cholesterol auto-oxidation, such as 7-ketocholesterol, play a key role in AD progression. Methods The brains were classified basing on Braak and Braak staging system of neurofibrillary pathology (early AD: stage 1 or 2; late AD: stage 4 to 6). In the control brains the presence of senile plaques and tau pathology was excluded. Oxysterols were measured by isotope dilution mass spectrometry. The inflammatory molecule expression was analyzed by qRT-PCR. Results A variety of oxysterols, both of enzymatic and non enzymatic origin, was identified and quantified in AD brains taking into account the different Braak and Braak stages of AD. The enhancement of few inflammatory mediators and the proteolitic enzyme MMP-9 was also demonstrated in the brains in agreement with the progression of the disease. Conversely, a marked reduction of sirtuin 1, an enzyme which regulates several pathways involved in the anti-inflammatory response, was observed with the progression of AD. Conclusion The pathogenic correlation between the amount of oxysterols in the AD brains and neuroinflammation is highlighted. Oxysterols could, thus, represent novel markers for the early diagnosis and progression of AD.