Identification of elevated levels of sestrin in early MCI and Alzheimer's disease: An opportunity for a potential marker Nitish Rai1, Amrendra Pratap Singh1, Shashank Shekhar1, A.B. Dey2, Sharmistha Dey1 1Department of Biophysics, 2Department of Geriatric Medicine, All India Institute of Medical Sciences, New Delhi - 110029, India One of the most common neurodegenerative disease, burdening the global economy, is Alzheimer's disease (AD). Impaired autophagy and endoplasmic reticulum (ER) stress has been identified early in AD even before the appearance of pathological hallmarks of amyloid β and tau aggregation . Sestrin (sesn) is an important regulator of autophagy and ER homeostasis by controlling target of rapamycin complex1 (TORC1). Sestrin belongs to a family of highly conserved stress-inducible protein known to protect cells against various insults including neurotoxic stress . Herein, we evaluated the level of sesn1 and sesn2 in the serum of, MCI (n=27), AD patients (n=41) and similar aged elderly controls (n=60) using surface plasmon resonance and western blot analysis. Also, the mRNA level of sesn was determined in the peripheral blood mononuclear cells (PBMCs) of patients and controls by real time PCR analysis. The estimation revealed a significantly increased levels of sesn2 in the serum of patients than in elderly control. Notably, the serum of MCI has elevated levels of sesn2 compared to control group. However, the levels of sesn1 in the serum of study groups was found to be unaltered. The western blot of albumin depleted serum also showed increased levels of sesn2 in MCI and AD but not in controls. The PBMCs of AD patients were found to possess remarkably higher (1.7 fold) sesn2 mRNA level compared to the PBMCs of control group. For marker based diagnosis of MCI and AD, the ROC curve was constructed which revealed a selective and sensitive cutoff value of sesn2. The elevated level of sesn2 in the serum of MCI and AD patients is a novel and promising finding. Further, the differential mRNA level of sestrin in AD patients also reveal a novel approach in a new direction of RNA marker assessment. The study emphasizes the importance of sesn2 in early diagnosis of AD which could slow the progression of this devastating disease and may prove vital in analysing the effectiveness of clinical trials.
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