Extracellular vesicles mediate inflammasome signaling in the brain and heart of Alzheimer's disease mice

Brianna Cyr; Erika D L R M Cabrera Ranaldi; Roey Hadad; W Dalton Dietrich; Robert W Keane; Juan Pablo de Rivero Vaccari

doi:10.3389/fnmol.2024.1369781

Extracellular vesicles mediate inflammasome signaling in the brain and heart of Alzheimer's disease mice

Front Mol Neurosci. 2024 Apr 10:17:1369781. doi: 10.3389/fnmol.2024.1369781. eCollection 2024.

Authors

Brianna Cyr¹, Erika D L R M Cabrera Ranaldi¹, Roey Hadad², W Dalton Dietrich¹, Robert W Keane^{1

2}, Juan Pablo de Rivero Vaccari^{1

2}

Affiliations

¹ Department of Neurological Surgery and The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, United States.
² Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, United States.

Abstract

Introduction: Alzheimer's disease (AD) is an inflammatory neurodegenerative disease characterized by memory loss and cognitive impairment that worsens over time. AD is associated with many comorbidities, including cardiovascular disease that are associated with poorer outcomes. Comorbidities, especially heart disease and stroke, play a significant role in the demise of AD patients. Thus, it is important to understand how comorbidities are linked to AD. We have previously shown that extracellular vesicle (EV)-mediated inflammasome signaling plays an important role in the pathogenesis of brain injury and acute lung injury after traumatic brain injury.

Methods: We analyzed the cortical, hippocampal, ventricular, and atrial protein lysates from APP/PS1 mice and their respective controls for inflammasome signaling activation. Additionally, we analyzed serum-derived EV for size, concentration, and content of inflammasome proteins as well as the EV marker CD63. Finally, we performed conditioned media experiments of EV from AD patients and healthy age-matched controls delivered to cardiovascular cells in culture to assess EV-induced inflammation.

Results: We show a significant increase in Pyrin, NLRP1, caspase-1, and ASC in the brain cortex whereas caspase-8, ASC, and IL-1β were significantly elevated in the heart ventricles of AD mice when compared to controls. We did not find significant differences in the size or concentration of EV between groups, but there was a significant increase of caspase-1 and IL-1β in EV from AD mice compared to controls. In addition, conditioned media experiments of serum-derived EV from AD patients and age-matched controls delivered to cardiovascular cells in culture resulted in inflammasome activation, and significant increases in TNF-α and IL-2.

Conclusion: These results indicate that EV-mediated inflammasome signaling in the heart may play a role in the development of cardiovascular diseases in AD patients.

Keywords: ASC; Alzheimer’s Disease; Extracellular Vesicles; caspase-1; heart; inflammasome; inflammation.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by an R01 grant from the NIH/NINDS to RK and JR (R01NS113969–01) and an RF1 grant from the NIH/NINDS/NIA (1RF1NS125578–01) to WD and JR.