Oxidative signature of cerebrospinal fluid from mild cognitive impairment and Alzheimer disease patients

• We analyzed oxidative modifications of the CSF proteome in aMCI and AD.
• Oxidatively modified proteins are already present in aMCI compared with controls and remain oxidized in AD.
• Increased carbonylation of target proteins occurs before severe dementia is diagnosed.
• Increased oxidation of Apolipoprotein E may favor Aβ oligomerization.
• Redox proteomics allows to identify potential molecular mechanisms involved in AD.

BackgroundSeveral studies suggest that pathological changes in Alzheimer’s disease (AD) brain begin around 10–20 years before the onset of cognitive impairment. Biomarkers that can support early diagnosis and predict development of dementia would, therefore, be crucial for patient care and evaluation of drug efficacy. Although cerebrospinal fluid (CSF) levels of Aβ42, tau, and p-tau are well-established diagnostic biomarkers of AD, there is an urgent need to identify additional molecular alterations of neuronal function that can be evaluated at the systemic level.ObjectivesThis study was focused on the analysis of oxidative stress-related modifications of the CSF proteome, from subjects with AD and amnestic mild cognitive impairment (aMCI).MethodsA targeted proteomics approach has been employed to discover novel CSF biomarkers that can augment the diagnostic and prognostic accuracy of current leading CSF biomarkers. CSF samples from aMCI, AD and control individuals (CTR) were collected and analyzed using a combined redox proteomics approach to identify the specific oxidatively modified proteins in AD and aMCI compared with controls.ResultsThe majority of carbonylated proteins identified by redox proteomics are found early in the progression of AD, i.e., oxidatively modified CSF proteins were already present in aMCI compared with controls and remain oxidized in AD, thus suggesting that dysfunction of selected proteins initiate many years before severe dementia is diagnosed.ConclusionsThe above findings highlight the presence of early oxidative damage in aMCI before clinical dementia of AD is manifested. The identification of early markers of AD that may be detected peripherally may open new prospective for biomarker studies.