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