A[beta].sub.25-35-induced autophagy and apoptosis are prevented by the CRMP2-derived peptide ST2-104 via a CaMKK[beta]/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; Apoptosis; Autophagy (Cytology); Care and treatment; Diagnosis; Health aspects; Peptides
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0309794

We previously reported that the peptide ST2-104 (CBD3, for Ca.sup.2+ channel-binding domain 3), derived from the collapsin response mediator protein 2 (CRMP2)-a cytosolic phosphoprotein, protects neuroblastoma cells against [beta]-amyloid (A[beta]) peptide-mediated toxicity through engagement of a phosphorylated CRMP2/NMDAR pathway. Abnormal aggregation of A[beta] peptides (e.g., A[beta].sub.25-35) 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 A[beta].sub.25-35 peptide and subsequently mapped the downstream signaling pathways involved. ST2-104 protected SH-SY5Y cells from death following A[beta].sub.25-35 peptide challenge by reducing apoptosis and autophagy as well as limiting excessive calcium entry. Cytotoxicity of SHY-SY5Y cells challenged with A[beta].sub.25-35 peptide was blunted by ST2-104. The autophagy activator Rapamycin blunted the anti-apoptotic activity of ST2-104. ST2-104 reversed A[beta].sub.25-35 -induced apoptosis via inhibiting Ca.sup.2+ /CaM-dependent protein kinase kinase [beta] (CaMKK[beta])-mediated autophagy, which was partly enhanced by STO-609 (an inhibitor of CaMKK[beta]). ST2-104 attenuated neuronal apoptosis by inhibiting autophagy through a CaMKK[beta]/AMPK/mTOR signaling hub. These findings identify a mechanism whereby, in the face of A[beta].sub.25-35, the concerted actions of ST2-104 leads to a reduction in intracellular calcium overload and inhibition of the CaMKK[beta]/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 (CaMKK[beta]/AMPK/mTOR) to confer neuroprotection in AD.