Abstract
Neuroinflammation caused by local deposits of Aβ42 in the brain is key for the pathogenesis and progression of Alzheimer’s disease. However, inflammation in the brain is not always a response to local primary insults. Gut microbiota dysbiosis, which is recently emerging as a risk factor for psychiatric disorders, can also initiate a brain inflammatory response. It still remains unclear however, whether enteric dysbiosis also contributes to Alzheimer’s disease. Here we show that in a Drosophila Alzheimer’s disease model, enterobacteria infection exacerbated progression of Alzheimer’s disease by promoting immune hemocyte recruitment to the brain, thereby provoking TNF-JNK mediated neurodegeneration. Genetic depletion of hemocytes attenuates neuroinflammation and alleviated neurodegeneration. We further found that enteric infection increases the motility of the hemocytes, making them more readily attracted to the brain with an elevated oxidative stress status. This work highlights the importance of gut–brain crosstalk as a fundamental regulatory system in modulating Alzheimer’s disease neurodegeneration.
Highlights
Neuroinflammation caused by local deposits of Aβ42 in the brain is key for the pathogenesis and progression of Alzheimer’s disease
Life span and locomotor activity are two important measures of Alzheimer’s disease (AD) symptoms, which are known to be significantly reduced in AD
One concern regarding these results was that the observed neurodegeneration-related phenotypes were caused by a direct enterobacteria infection spreading to the brain via a leaky intestinal barrier
Summary
Neuroinflammation caused by local deposits of Aβ42 in the brain is key for the pathogenesis and progression of Alzheimer’s disease. Our results showed that the Drosophila TNF eiger was readily upregulated in the brain of transgenic Aβ42 flies and being subjected to further dysregulation by enteric infection with Ecc[15] (Fig. 2a). Based on the results that both TNF and AMPs, the two key humoral innate immune components, were highly over-activated in the brain after enteric infection, we conclude that intestinal dysbiosis can remotely stimulate proinflammatory responses in the amyloid transgenic fly brain.
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