Intestinal microbial dysbiosis aggravates the progression of Alzheimer’s disease in Drosophila

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.

The role of gut microbiota in pathogenesis of Alzheimer's disease

“…Wu et al . () validated the vascular hypothesis by indicating that vascular degeneration caused locomotor activities to decline in the Drosophila . Finally, upon investigating whether the enteric impairments induced neuroinflammation, they found that Aβ 42 transgenic Drosophila had upregulated TNF Eiger levels.…”

“…More recently, one study has indicated that cerebrovascular pathology can trigger tau pathology, and accumulation in the cortex appears to account for cognitive impairments (Kim et al 2018). Wu et al (2017) validated the vascular hypothesis by indicating that vascular degeneration caused locomotor activities to decline in the Drosophila. Finally, upon investigating whether the enteric impairments induced neuroinflammation, they found that Ab 42 transgenic Drosophila had upregulated TNF Eiger levels.…”

“…In another human study, Cattaneo et al (2017) indicated that the numbers of Eubacterium rectale and Bacteroides fragilis organisms in patients with amyloidosis (Amy +) were significantly reduced as compared to the control group, while the number of Escherichia/Shigella organisms significantly increased, which supports the notion that AD affects the gut bacterial flora. Aside from the studies outlined above, a large number of studies have shown that gut microbes interact with the host in many respects (Bonfili et al 2017;Wu et al 2017;Ho et al 2018).…”

Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer’s disease-type beta-amyloid neuropathological mechanisms

“…There is tremendous diversity among individuals’ intestinal microbiota with respect to the composition of specific bacterial species and the density (number) of bacteria that are present for each of these bacterial species. Indeed, such interpersonal differences in intestinal bacteria composition have been associated with the presence or absence of an increasing number of health issues, including metabolic syndrome, obesity, immunological diseases, cardiovascular diseases, as well as neuro-degenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [1–4]. …”

Attenuation of epigenetic regulator SMARCA4 and ERK-ETS signaling suppresses aging-related dopaminergic degeneration

“…Measurement methods involved in were introduced from previously reported publications [12,13]. The Drosophila brains with different genetic backgrounds were live dissected and incubated with 10 μ M DCFDA for 5 min at RT if applicable, brain images were captured using a Leica TCS SP5 II confocal microscope with 488 nm excitation and 525 nm emission.…”