Accelerated APOA-II senile amyloidosis in a PAI-1 (plasminogen activator inhibitor 1) knock-out model

Apolipoprotein A-II amyloidosis (AApoA-II) is the most common form of age-related amyloidosis in mice, typically arising sporadically in aged animals or in senescence-accelerated strains carrying the APOA2C variant. Here, we report that plasminogen activator inhibitor-1 deficient (PAI-1 −/− ) mice develop systemic AApoA-II amyloidosis with complete penetrance at an intermediate age. Congo red-positive deposits were consistently observed after 12 months in multiple organs, including kidney, spleen, liver, heart, tongue, and intestine, whereas wild-type controls displayed significantly lower amyloid burden and penetrance. Injection of amyloid enhancing factor further accelerated disease onset. Mass spectrometry of purified fibrils and immunofluorescence identified APOA2 as the causative protein. Functional assessment revealed a strong correlation between renal amyloid burden and albuminuria, establishing urinary albumin as a reliable biomarker of disease evolution for preclinical studies. This model provides a robust and reproducible system for investigating age-related amyloidosis and for pre-clinical evaluation of anti-amyloid therapies. Although the role of PAI-1 deficiency in other forms of amyloidosis remains to be demonstrated, our findings raise concern that chronic PAI-1 inhibition, currently pursued in clinical programs, may inadvertently facilitate amyloid deposition by altering extracellular matrix remodeling. PAI-1 −/− mice thus represent both a valuable tool for amyloidosis research and a cautionary signal regarding therapeutic strategies targeting PAI-1.