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<div><p>We previously reported that the peptide ST2-104 (CBD3, for Ca<sup>2+</sup> 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., Aβ<sub>25–35</sub>) 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 Aβ<sub>25–35</sub> peptide and subsequently mapped the downstream signaling pathways involved. ST2-104 protected SH-SY5Y cells from death following Aβ<sub>25–35</sub> peptide challenge by reducing apoptosis and autophagy as well as limiting excessive calcium entry. Cytotoxicity of SHY-SY5Y cells challenged with Aβ<sub>25–35</sub> peptide was blunted by ST2-104. The autophagy activator Rapamycin blunted the anti-apoptotic activity of ST2-104. ST2-104 reversed Aβ<sub>25-35</sub>-induced apoptosis via inhibiting Ca<sup>2+</sup>/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 Aβ<sub>25–35</sub>, 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.</p></div>