Accruing evidence suggests that prion-like behavior of fibrillar forms of 
α-synuclein, β-amyloid peptide and mutant huntingtin are responsible for the 
spread of the lesions that characterize Parkinson disease, Alzheimer disease and 
Huntington disease, respectively. It is unknown whether these distinct protein 
assemblies are transported within and between neurons by similar or distinct 
mechanisms. It is also unclear if neuronal death or injury is required for 
neuron-to-neuron transfer. To address these questions, we used mouse primary 
cortical neurons grown in microfluidic devices to measure the amounts of 
α-synuclein, Aβ42 and HTTExon1 fibrils transported by axons in both directions 
(anterograde and retrograde), as well as to examine the mechanism of their 
release from axons after anterograde transport. We observed that the three 
fibrils were transported in both anterograde and retrograde directions but with 
strikingly different efficiencies. The amount of Aβ42 fibrils transported was 
ten times higher than that of the other two fibrils. HTTExon1 was efficiently 
transported in the retrograde direction but only marginally in the anterograde 
direction. Finally, using neurons from two distinct mutant mouse strains whose 
axons are highly resistant to neurodegeneration (Wld(S) and Sarm1(-/-)), we 
found that the three different fibrils were secreted by axons after anterograde 
transport, in the absence of axonal lysis, indicating that trans-neuronal spread 
can occur in intact healthy neurons. In summary, fibrils of α-synuclein, Aβ42 
and HTTExon1 are all transported in axons but in directions and amounts that are 
specific of each fibril. After anterograde transport, the three fibrils were 
secreted in the medium in the absence of axon lysis. Continuous secretion could 
play an important role in the spread of pathology between neurons but may be 
amenable to pharmacological intervention.