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.
Highlights
Introduction iationsHelicobacter pylori is a gastric pathogen known to infect approximately 60% of the world population, and in 2014 around 4.4 billion people were infected by this bacterium [1,2].In underdeveloped countries prevalence of 80% has been reported [3]
We found that the 7-day treatment with H. pylori’s urease (HPU) promoted a 9-fold increase (p = 0.0001) of tau phosphorylation at the S199 site (9.93 ± 0.01), similar to that of the LPStreated group (9.079 ± 0.209) when compared to the controls
It was observed that the death of SH-SY5Y cells depended on the activation of BV-2 cells, suggesting that microglia play an important role in
Summary
Helicobacter pylori is a gastric pathogen known to infect approximately 60% of the world population, and in 2014 around 4.4 billion people were infected by this bacterium [1,2]. In underdeveloped countries prevalence of 80% has been reported [3]. H. pylori infection is associated with several gastric pathologies, such as chronic gastritis, peptic and duodenal ulcers, gastric adenocarcinoma and lymphoma of the mucosa-associated lymphoid tissue [4]. Epidemiological studies correlate H. pylori infection with various extra gastrointestinal pathologies [5,6], such as ischemic heart disease [7], glaucoma [8], cerebrovascular diseases [9], autoimmune pancreatitis [10], and neurodegenerative diseases such as Alzheimer’s disease (AD) [11,12], mild cognitive impairment [13] and Parkinson’s disease [14,15]. In the case of AD, the correlation is based on the high incidence of H. pylori in these patients [12,16], as well as by the presence of anti-H. pylori antibodies.
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