Degeneration and repair in central nervous system disease

Abstract

Divergent disease triggers in neurodegeneration may induce convergent endogenous pathways in neuronal, glial and vascular elements as the central nervous system (CNS) attempts to compensate, remodel and recover. Dissecting these multicellular mechanisms and the integrative responses in cerebral blood flow and metabolism may allow us to understand the balance between injury and repair, validate new targets and define therapeutic time windows for neurodegeneration.

Figure 1

Endogenous responses, cofactors and therapeutic time windows in neurodegeneration. The wide spectrum of pathology in neurodegeneration reflects a multitude of initial triggers involved in the induction of disease. But divergent upstream mechanisms also lead to convergent downstream pathways as the brain responds to disease and injury. Endogenous responses of the CNS may comprise both deleterious and potentially beneficial mechanisms of inflammation and neurovascular remodeling. Non–cell-autonomous crosstalk between neuronal, glial and vascular compartments form the basis for these phenomena, and many cofactors influence the signals and substrates of these endogenous responses over time. Ultimately, prolonged inflammation and injury lead to a cumulative disease burden that outstrips any endogenous attempts at compensation or remodeling. Understanding these transitions may help define therapeutic time windows where candidate treatments for neurodegeneration should be more effective.