Brain-on-chip to investigate the role of red blood cells in age-associated neurodegeneration

Introduction: Neurodegenerative diseases represent a global burden for aging population. Aging and other hematological diseases have shown that alteration in the morphology of the erythrocytes (red blood cells/RBCs) have neurological implications. This suggests that the quality of RBCs have a crucial role to play in the neurodegeneration processes. The current challenges to treat neurodegenerative diseases include early diagnosis, lack of appropriate disease models for the drug testing process, and delivery of drugs across the blood-brain barrier. In this study, we aim a two-prong approach to address the current challenges.

Materials and

Methods: Primarily, we have developed a membrane-free, high throughput human brain-on-chip microfluidic device with TEER-integrated system. This brain-on-chip is a co-culture of human cerebral microvascular endothelial cells with human astrocytes, and human microglia. The brain-on-chip developed was used to determine the detrimental effects of the young and aging RBCs on the brain health.

Results, Conclusions, and Discussions: We found that the aging RBCs impair the integrity of the BBB in comparison to the young RBCs. Therefore, we conducted an extensive profiling the RBC-derived exosomal miRNAs of young and aging RBCs to investigate the role of RBCs in neurodegenerative diseases. Differential expression analysis of RBC-derived exosomal miRNAs from young and aging RBCs have identified downregulation of key signature miRNAs such as miR-let-7d, miR-142a, and miR-25 that have predicted gene targets in neuropathological processes. These results demonstrate the manifestations of the aging RBCs in neurodegeneration. The RBC-derived exosomal miRNA can serve as a potential blood-based biomarker for early diagnosis of neurodegenerative diseases.

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