# Biomolecular Aspects of Reelin in Neurodegenerative Disorders: An Old Candidate for a New Linkage of the Gut–Brain–Eye Axis

## TL;DR

This paper explores how Reelin, a glycoprotein, connects neurodegenerative diseases like AMD and Alzheimer’s with the gut–brain–eye axis, suggesting new pathways for understanding these conditions.

## Contribution

The paper proposes a novel hypothesis linking Reelin to the gut–brain–eye axis in neurodegenerative disorders.

## Key findings

- Reelin is dysregulated in AMD and Alzheimer’s, affecting synaptic function and neuroinflammation.
- AMD and Alzheimer’s share common risk factors and pathophysiological features, including oxidative stress and vascular issues.
- Reelin is produced in the gut, suggesting a role in the gut–brain–eye axis and microbiota interactions.

## Abstract

Recent findings highlight that Reelin, a glycoprotein involved in neural development, synaptic plasticity, and neuroinflammation, plays some specific roles in neurodegenerative disorders associated with aging, such as age-related macular degeneration (AMD) and Alzheimer’s disease (AD). Reelin modulates synaptic function and guarantees homeostasis in neuronal-associated organs/tissues (brain and retina). The expression of Reelin is dysregulated in these neurological disorders, showing common pathways depending on chronic neurogenic inflammation and/or dysregulation of the extracellular matrix in which Reelin plays outstanding roles. Recently, the relationship between AMD and AD has gained increasing attention as they share many common risk factors (aging, genetic/epigenetic background, smoking, and malnutrition) and histopathological lesions, supporting certain pathophysiological crosstalk between these two diseases, especially regarding neuroinflammation, oxidative stress, and vascular complications. Outside the nervous system, Reelin is largely produced at the gastrointestinal epithelial level, in close association with innervated regions. The expression of Reelin receptors inside the gut suggests interesting aspects in the field of the gut–brain–eye axis, as dysregulation of the intestinal microbiota has been frequently described in neurodegenerative and behavioral disorders (AD, autism, and anxiety and/or depression), most probably linked to inflammatory, neurogenic mediators, including Reelin. Herein we examined previous and recent findings on Reelin and neurodegenerative disorders, offering findings on Reelin’s potential relation with the gut–brain and gut–brain–eye axes and providing novel attractive hypotheses on the gut–brain–eye link through neuromodulator and microbiota interplay. Neurodegenerative disorders will represent the ground for a future starting point for linking the common neurodegenerative biomarkers (β-amyloid and tau) and the new proteins probably engaged in counteracting neurodegeneration and synaptic loss.