# Complement in brain and eye disease: shared mechanisms, convergent pathologies, and common therapeutic opportunities

## TL;DR

The brain and eye share similar immune mechanisms, and problems with the complement system contribute to diseases in both, offering shared therapeutic opportunities.

## Contribution

The paper highlights shared complement dysregulation in brain and eye diseases and suggests lessons from ocular treatments could aid brain therapies.

## Key findings

- Complement dysregulation contributes to neurodegeneration in both brain and eye diseases.
- Genetic variants in complement regulators affect susceptibility to both retinal and brain pathologies.
- Local complement activity modulates glial activation and vascular integrity in both organs.

## Abstract

The brain and eye share striking anatomical, physiological, and immunological similarities. Both are protected by specialised vascular barriers, the blood-brain barrier (BBB) and blood-retinal barrier (BRB) respectively, that maintain homeostasis through tightly regulated cellular and molecular mechanisms. Increasing evidence implicates complement dysregulation as a key driver of neurodegeneration in both organs, contributing to disorders such as Alzheimer’s disease (AD), and age-related macular degeneration (AMD). Genetic and molecular studies highlight overlapping mechanisms, with variants in complement regulators influencing susceptibility to both retinal and brain pathologies. Locally synthesised complement components modulate glial activation, vascular integrity, and synaptic remodelling at both sites and, when dysregulated, contribute to chronic inflammation, synapse loss and neuronal degradation. Despite these shared pathways, therapeutic development has progressed asymmetrically; several complement therapeutics are already in the clinic for AMD and other ocular pathologies, while none are yet in use for brain diseases. This is in part a consequence of the accessibility of the eye where complement targeted drugs can be directly delivered and impact on pathology monitored, difficult in the brain. Lessons learned from the eye, including local delivery to overcome challenges of barrier penetration, may help accelerate development of complement therapeutics for the brain. Here we present a brief perspective that integrates current understanding of complement-mediated mechanisms across brain and eye, emphasising clues from convergent pathophysiology and ocular translational successes.