Amyloid- Peptide Oligomers Disrupt Axonal Transport through an NMDA Receptor-Dependent Mechanism That Is Mediated by Glycogen Synthase Kinase 3 in Primary Cultured Hippocampal Neurons

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Abstract
Disruption of axonal transport is a hallmark of several neurodegenerative diseases, including Alzheimer9s disease (AD). Even though defective transport is considered an early pathologic event, the mechanisms by which neurodegenerative insults impact transport are poorly understood. We show that soluble oligomers of the amyloid-β peptide (AβOs), increasingly recognized as the proximal neurotoxins in AD pathology, induce disruption of organelle transport in primary hippocampal neurons in culture. Live imaging of fluorescent protein-tagged organelles revealed a marked decrease in axonal trafficking of dense-core vesicles and mitochondria in the presence of 0.5 μm AβOs. NMDA receptor (NMDAR) antagonists, including d-AP5, MK-801, and memantine, prevented the disruption of trafficking, thereby identifying signals for AβO action at the cell membrane. Significantly, both pharmacological inhibition of glycogen synthase kinase-3β (GSK-3β) and transfection of neurons with a kinase-dead form of GSK-3β prevented the transport defect. Finally, we demonstrate by biochemical and immunocytochemical means that AβOs do not affect microtubule stability, indicating that disruption of transport involves a more subtle mechanism than microtubule destabilization, likely the dysregulation of intracellular signaling cascades. Results demonstrate that AβOs negatively impact axonal transport by a mechanism that is initiated by NMDARs and mediated by GSK-3β and establish a new connection between toxic Aβ oligomers and AD pathology.