Helicobacter pylori Urease: Potential Contributions to Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) causes dementia and memory loss in the elderly. Deposits of beta-amyloid peptide and hyperphosphorylated tau protein are present in a brain with AD. A filtrate of Helicobacter pylori’s culture was previously found to induce hyperphosphorylation of tau in vivo, suggesting that bacterial exotoxins could permeate the blood–brain barrier and directly induce tau’s phosphorylation. H. pylori, which infects ~60% of the world population and causes gastritis and gastric cancer, produces a pro-inflammatory urease (HPU). Here, the neurotoxic potential of HPU was investigated in cultured cells and in rats. SH-SY5Y neuroblastoma cells exposed to HPU (50–300 nM) produced reactive oxygen species (ROS) and had an increased [Ca2+]i. HPU-treated BV-2 microglial cells produced ROS, cytokines IL-1β and TNF-α, and showed reduced viability. Rats received daily i.p., HPU (5 µg) for 7 days. Hyperphosphorylation of tau at Ser199, Thr205 and Ser396 sites, with no alterations in total tau or GSK-3β levels, and overexpression of Iba1, a marker of microglial activation, were seen in hippocampal homogenates. HPU was not detected in the brain homogenates. Behavioral tests were performed to assess cognitive impairments. Our findings support previous data suggesting an association between infection by H. pylori and tauopathies such as AD, possibly mediated by its urease.

Helicobacter Pylori-Vacuolating Cytotoxin A Inducing Neurotoxic Neuroinflammation in Human Stomach-Brain Axis

“…A previous study also showed indirect neuroinflammation in microglia via HP-stimulated stomach, elevating iNOS and NO [81]. Additionally, HPurease-stimulated microglia showed elevated ROS and cytokines such as IL-1β and TNF-α [82]. Building on prior limitations, our study validated central innate immunity responses, including microglia and astrocytes, upon HPCFS stimulation.…”

Probiotic supplement as a promising strategy in early tau pathology prevention: Focusing on GSK-3β?

“…These studies suggest that probiotics can directly act on GSK-3β pathway and alleviate tau hyperphosphorylation. Furthermore, probiotic has been proven effective in treating gastric infection caused by H. Pylori ( Aiba et al, 2015 ), which induces tau hyperphosphorylation in mouse hippocampal tissue ( Wang et al, 2014 ; Uberti et al, 2022 ), via the GSK-3β pathway ( Wang et al, 2014 ). Dysregulation of gut microbiota via gut-brain axis is associated with AD and probiotic supplement has the potential of correcting tau hyperphosphorylation through GSK-3β suppression.…”

Helicobacter pylori infection: a dynamic process from diagnosis to treatment

“…It was demonstrated that the pro-inflammatory properties of urease promote the transformation of endothelial cells into reactive oxygen species (ROS)-dependent differentiation programs that contribute to H. pylori infection ( de Jesus Souza et al., 2019 ). In addition to its strong association with various diseases, such as gastritis and peptic ulcer, previous research has established a link between the H. pylori urease and extragastric diseases, such as AD, which relates to the pro-inflammatory activity of urease and activation of the immune system, causing neuroinflammation and tau phosphorylation ( Uberti et al., 2022 ). Using urease inhibitors to suppress urease function is, therefore, a potentially promising strategy for eliminating H. pylori .…”