Reelin-mediated Signaling during Normal and Pathological Forms of Aging

Reelin is a large extracellular matrix protein essential for mediating proper neuronal positioning during development. Employing the same lipoprotein-mediated signaling cascade, Reelin regulates NMDA receptor homeostasis and modulates synaptic function and plasticity in adult synapses. In line, aging-related reduction in Reelin expression has been shown to contribute to cognitive impairments during normal aging. Although recent experimental evidence suggests an involvement of dysfunctional Reelin in pathological forms of aging, such as late-onset Alzheimer's disease (AD), the molecular mechanisms by which this conserved extracellular glycoprotein contributes to the pathogenesis of AD remains still largely unknown. In the present review, we briefly summarize the role of Reelin in the developing and adult brain and discuss the implication of loss-or gain-of-functions of developmental programs in the adult brain as putative inducing factors of pathological forms of aging. Finally, we will propose some new concepts on the role of inflammatory cytokines in interfering with Reelin-mediated signaling during neurodevelopment and adult synaptic function, and discuss how this could be translated into a novel non-transgenic mouse model of late-onset AD. Thus, the findings presented in this review are aimed to highlight the important role of Reelin-mediated signaling in maintaining a crucial developmental program in the adult brain that is required to prevent the shift from normal to pathological aging.