Background and Objective: Our goal is to obtain insight into the causes of the pathological lesions in Alzheimer’s disease (AD). It is thought that the β-amyloid (Aβ) deposits within the cerebral cortex and hippocampus of AD brains are initiated by a ‘bad seed’ of oligomeric Aβ. The origin of this seed is unknown. Here, we focused on the events that might trigger the formation of neuritic plaques, aiming to explain how these plaques form in cortical and hippocampal regions. Methods and Results: Using immunocytochemical and biochemical methods, we showed that brainstem-derived, neuronal cells (CAD) – but not cortical or hippocampal neurons – show large amounts of Aβ accumulated at the terminals of their processes. This is similar to what is believed to occur in brain neurons, in the early phases of AD. CAD cells that contain Aβ accumulations also concentrate β-secretase at process terminals. We show that, while the anterograde transport of small vesicles is not significantly affected, the mitochondrial transport is perturbed in CAD cells that contain Aβ accumulations. We further show that intracellular, neuritic Aβ accumulations may become extracellular upon neurite degeneration, thus providing the initial ‘bad seed’ of Aβ oligomers that triggers further aggregation of extracellular proteins. Conclusion: We propose that brainstem neurons, known to send projections throughout the brain, could provide the ‘bad seed’ of Aβ that nucleates plaques in the cerebral cortex and hippocampus of AD brains.

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