Alzheimer disease (AD), the main cause of senile dementia, is characterized by deposition of senile plaques, formed by Aß and tau protein aggregates, whose accumulation exerts neurotoxic effects. The diagnosis of AD is still largely based on exclusion criteria of secondary causes and other forms of dementia with similar clinical profile, thus the diagnostic accuracy is only suboptimal. Until now, no valid clinical method or biomarker is available to accurately identify AD in the very early phase and to determine which patient with mild cognitive impairment (MCI) will progress to AD. This is of special relevance because drug treatment is more effective in the early stage of the disease. Therefore, a valid and easy accessible biomarker for AD or a combination of biomarkers representing the multiplicity of pathophysiological processes taking place in AD would simplify the diagnosis, increase the accuracy and enhance the efficacy of drug therapy.
In this project we focus on lymphocytes as a peripheral cell model for AD and show similar defects like neurons in AD. Enhanced oxidative stress (OS) during aging and AD is not restricted to the brain but also present in peripheral cells, in fact several oxidative stress-related changes in lymphocytes have been observed related to aging. One of the redox-mediated posttraslational modifications (PTMs) is nitration (3-NT). Emerging evidences have certified that the occurrence of aberrant nitration of protein reactions could lead to protein misfolding, mitochondrial fission, synaptic damage, or apoptosis, thus contributing to the pathogenesis of AD. In light of these findings, we want evaluate the 3-NT status of proteins in lymphocytes obtained from AD patients using a proteomic approach. Thus, we have the possibility to understand, which protein or pathway is modified in lymphocytes of AD patients. Moreover, the identification of 3-NT modified proteins can help to identify an eventual biomarker for this pathology.
This is the first study that will analyse the 3-NT profile of proteins in lymphocytes isolated from AD patients. We develop a new approach for isolate 3-NT proteins which is more sensitive than normal redox proteomic approach. The results obtained will help to identify putative therapeutic targets to prevent/delay the development of AD in the general population. Understanding the onset of the altered 3 NT profile in AD lymphocytes may contribute to identification of key molecular regulators of age-associated cognitive decline in the pheripheral system. Considering the difficulty to analyze brain cells, it has been suggested that peripheral lymphocytes can provide biological markers to study the pathophysiology of AD. Although lymphocytes are highly specialized cells, they can represent the overall condition of the organism, since they circulate through the whole body and interact with several tissues. Moreover, the strong advantage of lymphocytes as a peripheral model compared to CSF is the simple non-invasive, inexpensive and time-saving separation from blood of patients. Repeated samples from patients can be taken as the particular study requires. Therefore, lymphocytes could be an applicable cell model to find a valid and easy detectable biomarker for AD.