Week VII

The focus this week has been on monocyte, DC, and T-cell trans endothelial/epithelial migration during inflammation. Though this phenomenon is not unique to prion disease, it is an important aspect to my model and connects it to other neurodegenerative diseases, like AD. ICAM-1 expression and subsequent ligation by a variety of proteins, like adherins expressed on the outer membrane of localized macrophages, attracted to sites of inflammation by afore mentioned inflammatory cytokines (IL-1β and TNFα), is important for transmigration of these gathered cells into the CNS and lymphatic system. ICAM-1 can also be the initial site for multiple signal transduction pathways including MAPK, ERK1/2, JNK, and activation of NF-κB. These pathways result in upregulation of  ICAM/VCAM  expression, cytokine release, Ca2+ efflux, and disruption of ECM. The disruption of the ECM is vital for the clustering component of ICAM-1, along with other proteins that aid monocyte/macrophage rolling and transmigration. The blood brain barrier is composed of endothelial cells that maintain a highly selective barrier between the blood and CNS with tight junctions (which include PECAM co-localized with endothelial-expressed PrPC, the implications of which have been previously discussed).  Cell can cross the barrier via two mediated paths: trans- and –paracellular migration. Paracellular migrations requires disruption of the tight leading to greater perforation of the BBB by migratory inflammatory cells, and greater damage in the CNS. One study claimed that though the method of choosing para vs. trans migration remains unclear, both have been witnessed during inflammation. It may be the T-cells prefers a paracellular route and monocytes prefer the trans. The internalization of ICAM-1 into caveosomes has been implemented in the transport of leukocytes into the endothelial cell, into MVBS, and released into the CNS in exosomes. The rate of each migration path need be elucidated; it may have a significant on the overall rate of disease pathogenesis as disruption of the BBB by continuous paracellular migration of leukocytes can increase the number of cells entering the CNS.