The contribution of initial concussive forces and resulting acrolein surge to β-amyloid accumulation and functional alterations in neuronal networks using a TBI-on-a-chip model
Edmond A. Rogers, Timothy Beauclair, Jhon Martinez, Shatha J. Mufti, David Kim, Siyuan Sun, Rachel L. Stingel, Alexandra M. Dieterly, Nikita Krishnan, Jennifer Crodian, Riyi Shi
Abstract
studies of trauma, while simultaneously validating the interaction of these alleged, key-pathological factors in post-TBI AD development. Specifically, we have shown that acrolein, acting as a diffusive factor of secondary injury, is both critical and sufficient in promoting inflammation (TNF-α) and Aβ42 aggregation, two known contributors of AD pathogenesis. Furthermore, using a cell-free preparation with TBI-on-a-chip, we have confirmed that both force and acrolein can independently and directly stimulate the aggregation of purified Aβ42, highlighting the key capabilities of primary and secondary injury mechanisms towards inducing Aβ42 aggregation, independently and synergistically. In addition to morphological and biochemical assessment, we also demonstrate parallel monitoring of neuronal network activity, further validating the chief pathological role of acrolein in not only inflicting biochemical abnormalities, but also functional deficits in neuronal networks. In conclusion, through this line of investigations, we have shown that by recapitulating clinically-relevant events, the TBI-on-a-chip device is capable of quantitatively characterizing parallel force-dependent increases in oxidative stress, inflammation, protein aggregation, and network activity, offering a unique platform for mechanistic investigations of post-TBI AD, and trauma-induced neuronal injury in general. It is expected that this model could provide crucial insights into pathological mechanisms which will be critical in developing novel, effective diagnostics and treatment strategies that significantly benefit TBI victims.