GPCR/moody reduction at the blood–brain barrier accelerates Alzheimer’s-like neurodegeneration in Drosophila

Abstract

The blood–brain barrier (BBB) is essential for maintaining central nervous system homeostasis by regulating the exchange of molecules between the brain and circulating blood. Dysfunction of this barrier has been implicated in the progression of several neurodegenerative disorders, including Alzheimer’s disease (AD). In this study, we investigated the role of BBB integrity in modulating AD-like pathology using a Drosophila melanogaster model. We generated an AD model by expressing human amyloid-β (hAβ 1–42 ) in all glial cells, which resulted in reduced lifespan, locomotor deficits, and amyloid plaque deposition. To induce BBB dysfunction, we selectively knocked down the G protein-coupled receptor moody in subperineurial glia (SPG), a key component of the Drosophila BBB. moody knockdown resulted in a significant increase in paracellular permeability without markedly altering hAβ 1–42 accumulation. However, BBB disruption exacerbated neurodegeneration, as evidenced by increased vacuole formation and apoptosis in the optic lobes, along with reduced neuropil size in both the medulla and mushroom body β lobes. Behavioural assays revealed that moody knockdown accelerated locomotor decline and increased seizure susceptibility in AD animals, whereas these effects were absent in flies lacking hAβ 1–42 expression. Together, our findings demonstrate a synergistic interaction between BBB dysfunction and amyloid toxicity, highlighting the protective role of BBB integrity against neurodegeneration. This study establishes Drosophila as a powerful model for dissecting neurovascular contributions to AD and underscores the importance of BBB maintenance in mitigating disease progression.