FIGURE 7:

Proposed mechanism for Ca²⁺-dependent disruption of dendritic and axonal BDNF transport. AβOs bind to dendrites and axons, enhancing Ca²⁺ influx through dendritic glutamate receptors and axonal VGCCs. In turn, this induces CICR from postsynaptic and presynaptic ER to elevate resting cytosolic Ca²⁺. Calmodulin binds free Ca²⁺ ions and subsequently activates CaN-GSK3β signaling in dendrites and axons. On activation, GSK3β may disrupt BDNF transport by directly phosphorylating and inhibiting motor proteins and/or disrupting motor–DCV interactions. Alternatively, a Ca²⁺-sensing adaptor protein may directly impair motor protein motility.