Targeting Caspases 3/6 and Cathepsins L/B May Decrease Laminopathy-Induced Apoptosis in Alzheimer’s Disease

Article type: Research Article

Authors: Rustamzadeh, Auob^{a; b} | Tafakhori, Abbas^c | Ariaei, Armin^d | Heydari, Mahdi^e | Shah-abadi, Mehran Ebrahimi^{f; 1; *} | Seif, Farhad^{g; 1; *}

Affiliations: [a] Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Department of Anatomical Sciences, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran | [b] Department of Anatomical Sciences, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran | [c] Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran | [d] Student Research Committee, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran | [e] Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran | [f] Department of Surgery, Afzalipour Hospital, Kerman University of Medical Sciences, Kerman, Iran | [g] Department of Photodynamic Therapy, Medical Laser Research Center, Academic Center for Education, Culture, and Research (ACECR), Tehran, Iran

Correspondence: [*] Correspondence to: Mehran Ebrahimi Shah-abadi, Department of Surgery, Afzalipour Hospital, P.O. Box: 7616913355, Kerman University of Medical Sciences, Kerman, Iran. E-mail: [email protected] and Farhad Seif, Enghelab St., P.O. Box: 1315673951, Aboureyhan St., Tehran, Iran. E-mail: [email protected].

Note: [1] These authors contributed equally as corresponding authors.

Abstract: Background:Laminopathy is a pathological manifestation observed in Alzheimer’s disease (AD), leading to neuronal apoptosis. Objective:Our objective was to assess inhibitors of enzymes involved in laminopathy. Methods:The mRNA expression of the cathepsins L and B, caspases 3 and 6, lamins b1 and b2, granzymes A and B, and lamins A and C were extracted and analyzed from GSE5281 and GSE28146 datasets. A total of 145 ligands were selected for molecular docking. Subsequently, 10 ns and 100 ns atomistic molecular dynamics (MD) and Martini 3 were performed with NAMD for two selected ligands (PubChem id: 608841 and ChEMBL id: 550872). Results:The mRNA expression level highlighted caspase 6 and lamin A/C upregulation in the hippocampus of the AD samples, in contrast to cathepsin B, lamin b2, and caspase 3. Moreover, there was a strong correlation between the expression level of cathepsin B, lamin A/C, and caspase 6 in the AD group. The MD results suggested molecule with ChEMBL id of 550872 had higher free binding energy, while in longer simulation the molecule with PubChem id of 608841 was suggested to be more stable in complex with the receptor. Conclusions:Our findings suggest that lamins A/C, cathepsins B/L, caspase 6, and lamin B2 are associated with laminopathy as potential factors contributing to apoptosis in AD. We propose that simultaneous inhibition of caspases 6 and cathepsins L may decrease the rate of apoptosis triggered by lamin degradation. Nevertheless, further studies are required to confirm these observations due to the lack of in vivo findings.

Keywords: Alzheimer’s disease, laminopathy, molecular dynamics, transcriptome

DOI: 10.3233/JAD-240413

Journal: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 211-221, 2024