Low-grade peripheral inflammation accelerates retinal amyloid pathology and dysfunction in an Alzheimer’s disease mouse model

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with increasing global prevalence. Although monoclonal antibody therapies targeting amyloid-beta (Aβ) have recently been approved, they provide only modest cognitive benefits and are associated with amyloid-related imaging abnormalities (ARIA), underscoring the need for further research. As AD is thought to begin decades before clinical symptoms emerge, early diagnosis and intervention have become critical. In this context, the retina, an accessible extension of the central nervous system (CNS), offers a promising platform for non-invasive, longitudinal monitoring of AD-related changes. In this study, we examined the impact of low-grade peripheral inflammation, induced by repeated intraperitoneal lipopolysaccharide (LPS) injections, on retinal pathology in wild-type and AppNL−G−F mice, a knock-in AD model. This approach reflects a growing recognition that environmental factors such as systemic inflammation contribute to AD progression in the brain, highlighting the need to integrate both genetic and environmental influences into preclinical models. Consistent with this, LPS triggered transient retinal neuroinflammation in wild-type mice, whereas AppNL−G−F mice exhibited prolonged Müller glia reactivity, and accelerated Aβ plaque formation accompanied by local microglial activation. Correspondingly, visual function tests and electrophysiological analysis revealed temporary retinal dysfunction in wild-type mice and sustained, widespread electrophysiological deficits accompanied by loss of vision in AppNL−G−F mice, despite no evidence of persistent neuronal cell loss or synaptic degeneration. Together, these findings demonstrate that, while peripheral inflammation is known to aggravate brain pathology in AD, it can also exacerbate retinal Aβ pathology and neuronal dysfunction in genetically susceptible mice. This underscores the retina’s potential as a sensitive site for early detection and the importance of accounting for both genetic and environmental factors in AD modelling.