Bacterial Amyloid Curli Associated Gut Epithelial Neuroendocrine Activation Predominantly Observed in Alzheimer’s Disease Mice with Central Amyloid-β Pathology

Abstract

Background: Substantial evidence from recent research suggests an influential and underappreciated force in Alzheimer’s disease (AD) pathogenesis: the pathological signals originate from outside the brain. Pathogenic bacteria produce amyloid-like proteins “curli” that form biofilms and show functional similarities to human amyloid-β (Aβ). These proteins may contribute to neurological disease progression via signaling cascade from the gut to the brain. Objective: We propose that curli causes neuroendocrine activation from the gut to brain that promotes central Aβ pathology. Methods: PGP9.5 and TLR2 levels in response to curli in the lumen of Tg2576 AD mice were analyzed by immunohistochemical and qRT-PCR analysis. Western blot and human 3D in vitro enteroids culture systems were also used. 16S rRNA gene sequencing was used to investigate bacterial dysbiosis. Results: We found significant increase in bacterial-amyloid curli with elevated TLR2 at the mRNA level in the pre- and symptomatic Tg-AD gut compared to littermate WT controls. This data associates with increased gram-positive bacterial colonization in the ileum of the symptomatic AD mice. We found fundamental evidence for vagus nerve activation in response to bacterial curli. Neuroendocrine marker PGP9.5 was significantly elevated in the gut epithelium of symptomatic AD mice, and this was colocalized with increased TLR2 expression. Enteroids, 3D-human ileal mini-gut monolayer in vitro model system also revealed increase levels of TLR2 upon stimulation with purified bacterial curli fibrils. Conclusion: These findings reveal the importance of pathological changes within the gut-vagus-brain signaling in response to luminal bacterial amyloid that might play a vital role in central Aβ pathogenesis seen in the AD brain.

The potential of the gut microbiome for identifying Alzheimer’s disease diagnostic biomarkers and future therapies

“…Previous studies have found that stimulatory signals from the gut and vagus nerve activate the hypothalamic–pituitary–adrenal axis and promote corticosterone release ( Zimomra et al, 2011 ), leading to changes in intestinal permeability ( Moussaoui et al, 2014 ), dynamics ( Gue et al, 1991 ), and mucus ( Silva et al, 2014 ). In addition, recent studies have also revealed the importance of pathological changes in the gut-vagus-brain signaling pathway in AD ( Das et al, 2022 ). These findings further suggest a critical role for vagal signaling as a bridge between peripheral and central crosstalk.…”

Disease- and stage-specific alterations of the oral and fecal microbiota in Alzheimer's disease

“…It shows similarities to human Aβ and α-synuclein which is implicated in Parkinson's disease and may contribute to pathology through immune activation via systemic or vagal pathways ( 84 ). So far, animal experiments showed a higher abundance of Curli in AD and Parkinson's disease mouse models ( 85 , 86 ); however, substantiation of these patterns in humans is still lacking behind, particularly for AD. Immunological responses to Curli are highly site specific, provoking proinflammatory reactions in systemic infections while leading to intestinal anti-inflammatory and barrier-restoring reactions when administered orally ( 87 , 88 ).…”

Interlink between the gut microbiota and inflammation in the context of oxidative stress in Alzheimer’s disease progression

“…Recently, we found that the integrity of the gut barrier was markedly decreased in Tg2576 AD mice which might increase bacterial amyloid (curli) burden in the gut before the appearance of Aβ deposition in the brain. 87 Curli stimulated TLR2 activation and co-localized with neuroendocrine marker PGP 9.5 within the epithelium and sub-mucosa of the gut in AD mice. 87 It indicated the vagus nerve activation by bacterial curli.…”

“… 87 Curli stimulated TLR2 activation and co-localized with neuroendocrine marker PGP 9.5 within the epithelium and sub-mucosa of the gut in AD mice. 87 It indicated the vagus nerve activation by bacterial curli. Therefore, activation of TLR2 can stimulate AD pathogenesis 87 , 88 , 92 , 102 It indicates that inhibition of TLR2 from periphery might be beneficial for AD.…”

“… 87 It indicated the vagus nerve activation by bacterial curli. Therefore, activation of TLR2 can stimulate AD pathogenesis 87 , 88 , 92 , 102 It indicates that inhibition of TLR2 from periphery might be beneficial for AD. In-vivo and in-vitro studies also showed that phagocytosis and Aβ clearance in microglia were increased by the deficiency of TLR2 89 .…”