Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases

Reelin is a conserved extracellular glycoprotein crucial for neurodevelopment. In adulthood, Reelin is an important modulator of NMDA receptor-mediated neurotransmission, required for synaptic plasticity, learning and memory. Consequently, abnormal Reelin-mediated signaling has been associated with many human brain disorders involving directly or indirectly altered NMDA receptor function. For most neurological and neuropsychiatric disorders, abnormalities during brain development appear central in the disease etiology. However, a similar causative relationship for neurodegenerative diseases, like Alzheimer's disease (AD), has not been investigated yet. The findings reviewed here center around the hypothesis that dysfunctional Reelin-mediated signaling converges overlapping molecular pathogenic pathways in schizophrenia and AD; highlighting a surprising interaction between prenatal inflammation and developmental abnormalities that appear to play a common role in aging-related neuropathology and cognitive decline. I hypothesize that the progression from normal aging to AD possibly results from late-gestational misregulations of inflammatory cytokines, resulting in immediate neuronal loss of Reelin-expressing neurons, facilitation of protein aggregation and concomitant impairments in proteolytical degradation during adulthood and aging, accompanied by chronic inflammation, expected to induce neurodegenerative processes. Conversely, a developmental immune challenge during mid-gestation, shown to preferentially mimic schizophrenia-like behavioural and neurochemical abnormalities, including impaired Reelin-mediated signaling, prevents progressive neurodegeneration, potentially linked to the immature embryonic immune system at the time of insult, which occludes long-term changes and sub-chronic elevations of inflammatory cytokines. Thus, the findings presented in this review suggest that schizophrenia can indeed be described as a form of accelerated aging or "dementia praecox" as first described by Emil Kraepelin in 1906.