Constrictions and shear stress are key determinants of amyloidogenic light chain (AL) amyloidosis.

Amyloid fibrils, crystal-like aggregates of denatured proteins, form upon breakdown of supersaturation and underlie amyloidosis in diseases, such as Alzheimer's, Parkinson's, and amyloidogenic light chain (AL) disease. In AL amyloidosis, fibrils accumulate in the heart, where they are exposed to shear stress. To mimic cardiac amyloidosis, where each heartbeat causes diameter fluctuations in coronary arterioles, we employ a peristaltic pump using the same mechanical principle to induce shear stress, combined with thioflavin T fluorescence microscopy for in situ real-time observation of amyloid formation of an AL protein associated with heart amyloidosis. Our results demonstrate that confined geometries amplify shear stress-dependent amyloid nucleation. Furthermore, using grid-type microchannels to model arteriole networks under shear stress, we observed fluorescent amyloid bursts reflecting dynamic pathways shaped by fibril deposition, local mechanical stress, and channel occlusion. We also observed that mechanical agitation using a micromanipulator, in conjunction with disaggregating agents, was effective for removing amyloid deposits. Collectively, our findings reveal key principles underlying shear stress-dependent amyloid formation and provide a novel framework for understanding amyloid deposition in organs, potentially advancing anti-amyloidosis strategies.