Reelin is a large extracellular glycoprotein that has garnered scientific interest for its widespread influence on brain function. It plays a significant role in both the developing and adult brain, regulating cellular processes that underpin neurological health. Researchers are exploring Reelin’s involvement in various brain conditions, recognizing its potential as a target for future therapeutic interventions.
Understanding Reelin’s Natural Role
Reelin, a large extracellular glycoprotein, is fundamental to brain formation and operation. During embryonic development, Reelin is primarily secreted by Cajal-Retzius cells and directs the migration of neurons, ensuring they settle in their correct positions to form the layered structures of the cerebral cortex and cerebellum. This precise neuronal placement is essential for establishing functional brain circuitry.
In the adult brain, Reelin’s expression shifts, becoming prominent in GABAergic interneurons of the cortex and hippocampus. Here, it continues to modulate synaptic plasticity, the ability of neuronal connections to strengthen or weaken over time. This modulation of synaptic plasticity is closely linked to learning and memory processes. Reelin also participates in adult neurogenesis, the creation of new neurons, particularly in the hippocampus, influencing the positioning and dendritic development of these newly formed cells.
Reelin exerts its effects by binding to specific receptors on the surface of neurons, primarily Apolipoprotein E receptor 2 (ApoER2) and Very Low-Density Lipoprotein Receptor (VLDLR). This binding initiates a complex intracellular signaling cascade involving kinases like Src and Fyn, and the adaptor protein Disabled-1 (Dab1). This signaling pathway ultimately influences the regulation of N-methyl-D-aspartate receptor (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) activity, crucial for synaptic transmission and plasticity.
Reelin’s Link to Brain Health
Alterations in Reelin levels or its signaling pathway have been associated with several neurological and psychiatric conditions, highlighting its broad impact on brain health. In Alzheimer’s disease (AD), disruptions in Reelin signaling are correlated with hallmark features such as amyloid-beta accumulation and tau hyperphosphorylation. Reelin signaling is thought to negatively regulate AD-associated neuropathology; defects in Reelin, ApoER2, or VLDLR can increase hyperphosphorylated tau levels.
Schizophrenia is another condition where altered Reelin expression is observed, particularly reduced levels in certain brain regions like the superior frontal cortex, parietal cortex, and cerebellum. These changes in Reelin signaling, including epigenetic modifications affecting the Reelin gene (RELN) expression, are linked to disruptions in neuronal development and synaptic plasticity, impairing neuronal connectivity and contributing to cognitive deficits in schizophrenia.
Furthermore, Reelin dysfunction has been implicated in autism spectrum disorder (ASD). Studies have shown reduced levels of Reelin protein, including its fragments, in the cerebella and superior frontal and parietal cortices of individuals with autism. This pervasive disruption of brain cytoarchitecture, including disorganization of the hippocampus and amygdala, suggests a link between reduced Reelin expression and neurological anomalies in ASD. The mechanisms by which Reelin dysfunction contributes to these conditions often relate to its roles in synaptic plasticity and neuronal migration.
Reelin as a Potential Therapeutic Target
Modulating Reelin’s activity or levels is a promising area for therapeutic research. However, direct Reelin protein supplements are not widely available or proven for human use, as the scientific community is currently exploring various strategies to influence Reelin signaling.
One approach involves the use of gene therapy to introduce or enhance Reelin expression in specific brain regions. Preclinical studies in animal models, such as mouse models of amyloid-induced tauopathy, show that injecting a bioactive fragment of Reelin via gene therapy can partially protect against cognitive impairment. This suggests a potential neuroprotective role for Reelin signaling in conditions like Alzheimer’s disease, as it reduced insoluble amyloid-beta 42, though it did not directly reduce tau pathology.
Researchers are also investigating small molecules that can indirectly modulate Reelin activity or its downstream signaling pathways. These molecules could overcome challenges associated with delivering large protein molecules like Reelin across the blood-brain barrier, a protective layer that restricts many substances from entering the brain. Indirect agonists that enhance the effects of naturally occurring Reelin are also under investigation.
While the research is promising, Reelin-based therapies are still in the preclinical or early clinical trial stages. The complexity of Reelin’s signaling pathways and the challenges of targeted delivery within the brain necessitate extensive further research. Future human clinical trials are required to determine the safety, efficacy, and appropriate dosage for any Reelin-modulating interventions before they could be considered as viable treatments for neurological and psychiatric conditions.