Circulatory GSK-3β: Blood-Based Biomarker and Therapeutic Target for Alzheimer’s Disease

Article type: Research Article

Authors: Kumari, Shiwani^{a; 1} | Singh, Ambica^{b; 1} | Singh, Abhinay Kumar^a | Yadav, Yudhishthir^a | Bajpai, Swati^b | Kumar, Pramod^b | Upadhyay, Ashish Datt^c | Shekhar, Shashank^a | Dwivedi, Sadanand^c | Dey, A.B.^b | Dey, Sharmistha^{a; *}

Affiliations: [a] Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India | [b] Department of Geriatric Medicine, All India Institute of Medical Sciences, New Delhi, India | [c] Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India

Correspondence: [*] Correspondence to: Dr. Sharmistha Dey, Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India. Tel.: +91 11 2659 6435; Fax: +91 11 2658 8663; E-mail: sharmistha_d@hotmail.com.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Alzheimer’s disease (AD) is the progressive brain disorder which degenerates brain cells connection and causes memory loss. Although AD is irreversible, it is not impossible to arrest or slow down the progression of the disease. However, this would only be possible if the disease is diagnosed at an early stage, and early diagnosis requires clear understanding of the pathogenesis at molecular level. Overactivity of GSK-3β and p53 accounts for tau hyperphosphorylation and the formation of amyloid-β plaques. Objective:Here, we explored GSK-3β and p53 as blood-based biomarkers for early detection of AD. Methods:The levels of GSK-3β, p53, and their phosphorylated states were measured using surface plasmon resonance and verified using western blot in serum from AD, mild cognitive impairment (MCI), and geriatric-control (GC) subjects. The neurotoxic SH-SY5Y cell line was treated with antioxidant Emblica Officinalis (EO) for rescue effect. Results:GSK-3β, p53, and their phosphorylated states were significantly over expressed (p > 0.001) in AD and MCI compared to GC and can differentiate AD and MCI from GC. The expression level of GSK-3β and p53 proteins were found to be downregulated in a dose-dependent manner after the treatment with EO in amyloid-b-induced neurotoxic cells. Conclusion:These proteins can serve as potential blood markers for the diagnosis of AD and EO can suppress their level. This work has translational value and clinical utility in the future.

Keywords: Alzheimer’s disease, Emblica Officinalis, GSK-3β, mild cognitive impairment, protein biomarker, SH-SY5Y , surface plasmon resonance

DOI: 10.3233/JAD-215347

Journal: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 249-260, 2022