β‐Amyloid is transmitted via neuronal connections along axonal membranes

Objective β‐amyloid plaque is a critical pathological feature of Alzheimer disease. Pathologic studies suggest that neurodegeneration may occur in a retrograde fashion from axon terminals near β‐amyloid plaques, and that plaque may spread through brain regions. However, there is no direct experimental evidence to show transmission of β‐amyloid. Methods Microscopic imaging data of β‐amyloid transmission was acquired in cortical neuron cultures from Sprague‐Dawley rat embryos using polydimethylsiloxane (PDMS) microfluidic culture chambers and in brain sections from in vivo β‐amyloid injection. Results We present direct imaging evidence in cultured cortical neurons, using PDMS microfluidic culture chambers, that β‐amyloid is readily absorbed by axonal processes and retrogradely transported to neuronal cell bodies. Transmission of β‐amyloid via neuronal connections was also confirmed in mouse brain. β‐Amyloid absorbed by distal axons accumulates in axonal swellings, mitochondria, and lysosomes of the cell bodies. Interestingly, dynasore, an inhibitor of dynamin, which is a protein indispensable for endocytosis, did not prevent retrograde transport of β‐amyloid, indicating that β‐amyloid is absorbed onto axonal membranes and transmitted via them to the cell body. Dynasore did decrease the transneuronal transmission of β‐amyloid, suggesting that this requires the internalization and secretion of β‐amyloid. Interpretation Our findings provide direct in vitro and in vivo evidence for spreading of β‐amyloid through neuronal connections, and suggest possible therapeutic approaches to blocking this spread. Ann Neurol 2014;75:88–97