"Cyclophilin A" Enzymatic Effect on the Aggregation Behavior of 1N4R Tau Protein: An Overlooked Crucial Determinant that should be Re-considered in Alzheimer's Disease Pathogenesis


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Abstract

Background:Neurodegenerative disorders like Alzheimer's disease (AD) involve the abnormal aggregation of tau protein, which forms toxic oligomers and amyloid deposits. The structure of tau protein is influenced by the conformational states of distinct proline residues, which are regulated by peptidyl-prolyl isomerases (PPIases). However, there has been no research on the impact of human cyclophilin A (CypA) as a PPIase on (non-phosphorylated) tau protein aggregation.

Methods:On the basis of these explanations, we used various spectroscopic techniques to explore the effects of CypA on tau protein aggregation behavior.

Results:We demonstrated the role of the isomerization activity of CypA in promoting the formation of tau protein amyloid fibrils with well-defined and highly ordered cross-β structures. According to the \"cistauosis hypothesis,\" CypA's ability to enhance tau protein fibril formation in AD is attributed to the isomerization of specific proline residues from the trans to cis configuration. To corroborate this theory, we conducted refolding experiments using lysozyme as a model protein. The presence of CypA increased lysozyme aggregation and impeded its refolding process. It is known that proper refolding of lysozyme relies on the correct (trans) isomerization of two critical proline residues.

Conclusion:Thus, our findings confirmed that CypA induces the trans-to-cis isomerization of specific proline residues, ultimately leading to increased aggregation. Overall, this study highlights the emerging role of isomerization in tau protein pathogenesis in AD.

About the authors

Samira Ranjbar

Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences

Email: info@benthamscience.net

Masomeh Mehrabi

Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences

Author for correspondence.
Email: info@benthamscience.net

Vali Akbari

Department of Biology, Faculty of Basic Sciences, Lorestan University

Email: info@benthamscience.net

Somayeh Pashaei

Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences

Email: info@benthamscience.net

Reza Khodarahmi

Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences

Author for correspondence.
Email: info@benthamscience.net

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