Selective cellular vulnerability and resilience in amyloidosis: insights from the 2025 International Society of Amyloidosis Workshop.

BACKGROUND: Amyloidosis is characterized by hierarchical organ-specific targeting related to the nature and amino acid sequence of the precursor protein. However, several crucial aspects of tissue vulnerability and resilience to amyloid deposition and toxicity remain poorly defined. RESULTS: The amino acid sequence of the amyloid protein is a primary determinant of organ targeting. Cryo-electron microscopy reveals common fibril architectures across organs, indicating interactions with shared tissue constituents. The interaction with the microenvironment, comprising glycosaminoglycans, collagen, endoproteases, and tissue cells, may underlie tissue vulnerability. Cellular interactions involve internalization of amyloid precursors, leading to lysosomal dysfunction, mitochondrial impairment, reactive oxygen species production, and proteotoxicity, particularly in cardiomyocytes and mesangial cells. Increased structural dynamics in amyloidogenic light chains promote improper interactions with cell constituents. Tissue-specific proteostasis capacity declines with age, contributing to tissue vulnerability in elderly patients. Parallels with neurodegenerative diseases underscore selective cellular susceptibility due to proteostatic overload and metabolic stress. CONCLUSIONS: Evidence shows that the amino acid sequence of the amyloid protein, microenvironmental factors, and cell-intrinsic and extracellular proteostatic capacity jointly determine tissue vulnerability and resilience in amyloidosis, with relative contributions varying by amyloid protein. Identifying key determinants provides actionable targets for improving the care of systemic and localized amyloidosis.