Aβ25-35-induced autophagy and apoptosis are prevented by the CRMP2-derived peptide ST2-104 (R9-CBD3) via a CaMKKβ/AMPK/mTOR signaling hub

• Published in: PloS one 2024-09, Vol.19 (9), p.e0309794
• Main Authors: Ji, Yingshi, Ren, Jinghong, Qian, Yuan, Li, Jiaxin, Liu, Huanyu, Yao, Yuan, Sun, Jianfeng, Khanna, Rajesh, Sun, Li
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; AMP-Activated Protein Kinases - metabolism; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - toxicity; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Biology and Life Sciences; Calcium; Calcium (intracellular); Calcium - metabolism; Calcium channels; Calcium ions; Calcium signalling; Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism; Cell death; Cell Line, Tumor; Collapsin response mediator protein 2; Cytotoxicity; Disease; Glutamate receptors; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Intracellular signalling; Ischemia; Kinases; Mediator protein; Medicine and Health Sciences; Morphology; N-Methyl-D-aspartic acid receptors; Nerve Tissue Proteins - metabolism; Neuroblastoma; Neuroblasts; Neurodegenerative diseases; Neurons; Neuroprotection; Peptide Fragments - metabolism; Peptide Fragments - toxicity; Peptides; Proteins; Rapamycin; Research and Analysis Methods; Signal transduction; Signal Transduction - drug effects; TOR protein; TOR Serine-Threonine Kinases - metabolism; Toxicity; β-Amyloid
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0309794

We previously reported that the peptide ST2-104 (CBD3, for Ca2+ channel-binding domain 3), derived from the collapsin response mediator protein 2 (CRMP2)-a cytosolic phosphoprotein, protects neuroblastoma cells against β-amyloid (Aβ) peptide-mediated toxicity through engagement of a phosphorylated CRMP2/NMDAR pathway. Abnormal aggregation of Aβ peptides (e.g., Aβ25-35) leads to programmed cell death (apoptosis) as well autophagy-both of which contribute to Alzheimer's disease (AD) progression. Here, we asked if ST2-104 affects apoptosis and autophagy in SH-SY5Y neuroblastoma challenged with the toxic Aβ25-35 peptide and subsequently mapped the downstream signaling pathways involved. ST2-104 protected SH-SY5Y cells from death following Aβ25-35 peptide challenge by reducing apoptosis and autophagy as well as limiting excessive calcium entry. Cytotoxicity of SHY-SY5Y cells challenged with Aβ25-35 peptide was blunted by ST2-104. The autophagy activator Rapamycin blunted the anti-apoptotic activity of ST2-104. ST2-104 reversed Aβ25-35-induced apoptosis via inhibiting Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ)-mediated autophagy, which was partly enhanced by STO-609 (an inhibitor of CaMKKβ). ST2-104 attenuated neuronal apoptosis by inhibiting autophagy through a CaMKKβ/AMPK/mTOR signaling hub. These findings identify a mechanism whereby, in the face of Aβ25-35, the concerted actions of ST2-104 leads to a reduction in intracellular calcium overload and inhibition of the CaMKKβ/AMPK/mTOR pathway resulting in attenuation of autophagy and cellular apoptosis. These findings define a mechanistic framework for how ST2-104 transduces "outside" (calcium channels) to "inside" signaling (CaMKKβ/AMPK/mTOR) to confer neuroprotection in AD.