Gut bacterial toxin further enhances blood-brain barrier alterations in a progressive mouse model of Parkinson’s disease

There is increasing evidence for dysfunction of blood-brain barrier (BBB) to play a critical role in the pathological mechanisms and progression of Parkinson’s disease (PD). PD-related pathology such as alpha-synuclein (aSyn) accumulation potentially affects the integrity of the BBB starting at an early disease stage. This could result in a self-perpetuating pathophysiology of inflammation and BBB alteration, which contributes to neurodegeneration.In our initial study, we described microvascular changes during disease progression in a mouse model with overexpression of human aSyn (Thy1-aSyn, line 61, Lau et al., Neurobiol Dis 2023). This model replicates characteristic symptoms of PD, aSyn pathology and dopamine loss. BBB alterations observed in Thy1-aSyn mice included altered transporter protein expression, and increased endothelial activation. However, these alterations of BBB integrity, did not lead to an overt IgG leakage into brain parenchyma.Now we present a study that aimed to decipher whether these BBB alterations in Thy1-aSyn mice render this model more vulnerable to additional inflammatory processes such as a single injection of the bacterial toxin lipopolysaccaride (LPS). Two weeks after modeling a transient gut dysbiosis we measured leakage of i.v. injected albumin-Fluorescein-Isothiocyanat-Konjugat (FITC-albumin). Brains from animals treated with LPS showed higher fluorescent intensity after receiving FITC-albumin. We analyzed peripheral immune cell invasion as well as border-associated macrophages.Our data reveal that BBB alterations in aSyn over-expressing mice are exacerbated by a bacterial toxin, replicating a transient gut dysbiosis. Enhanced leakage across the BBB suggests immune cell invasion, which could drive neuroinflammation.