Reelin Signaling in Neurodevelopmental Disorders and Neurodegenerative Diseases

Abstract

Reelin is an extracellular matrix glycoprotein involved in neuronal migration during embryonic brain development and synaptic plasticity in the adult brain. The role of Reelin in the developing central nervous system has been extensively characterized. Indeed, a loss of Reelin or a disruption in its signaling cascade leads to neurodevelopmental defects and is associated with ataxia, intellectual disability, autism, and several psychiatric disorders. In the adult brain, Reelin is critically involved in neurogenesis and synaptic plasticity. Reelin’s signaling potentiates glutamatergic and GABAergic neurotransmission, induces synaptic maturation, and increases AMPA and NMDA receptor subunits’ expression and activity. As a result, there is a growing literature reporting that a loss of function and/or reduction of Reelin is implicated in numerous neurodegenerative diseases. The present review summarizes the current state of the literature regarding the implication of Reelin and Reelin-mediated signaling during aging and neurodegenerative disorders, highlighting Reelin as a possible target in the prevention or treatment of progressive neurodegeneration.

Reelin Signaling and Synaptic Plasticity in Schizophrenia

“…Disruption of the signal transduction pathway, initiated by reelin, has a detrimental impact on the morphology of the cortical areas of the brain [13][14][15][16][17][18][19][20][21][22]26,[50][51][52][53][54]72,[80][81][82]84,116].…”

“…Because reelin regulates the neuroblast cytoarchitecture, including the migration and positioning of pyramidal neurons, interneurons, and Purkinje cells, and, after birth, still modulates synaptic plasticity, it has become one of the obvious candidates for a neurodevelopmental hypothesis of schizophrenia [77][78][79][80][81][82]. Importantly, in the neurodevelopmental hypothesis, the disease is the result of the confluence of various factors, biological and psychosocial, acting sequentially at two critical milestones (two-hit model), i.e., initial early damage at the end of the first or second trimester of pregnancy, e.g., as a result of viral infection or psychosocial stress, and then the clinical manifestation of the disease in early adulthood, cumulatively after the final phase of puberty in the presence of individual predispositions and modifying factors, e.g., genetic, familial, psychoactive drug-related or others [81,82].…”

The Single Toxin Origin of Alzheimer’s Disease and Other Neurodegenerative Disorders Enables Targeted Approach to Treatment and Prevention

“…Recent studies have highlighted the APOE4 interaction with the Reelin-Disabled-1 (Dab1) signaling pathway, which plays a protective role in synaptic development and plasticity [ 82 ]. Reelin signaling protects synapses from Aβ-induced neuronal stress, while APOE4 interferes with this protective effect, worsening synaptic toxicity of Aβ [ 83 ].…”

Unveiling the Relationship between Cannabidiol, Apo-lipoprotein and Neurological Disorders: A Comprehensive Review of Molecular Targets and Current Findings

“…This effect was mediated through the cannabinoid receptor 2 (CB2R) and involved the activation of the PI3K/AKT pathway. 37 CBD has also been shown to regulate TREM2 and IL-33, which are associated with improved cognitive function. The TREM2-ApoE system plays a crucial role in the microglial clearance of various extracellular and intracellular debris, thereby potentially reducing neuronal damage in the neurodegenerative environment.…”