鈥淲e detected Gram-negative bacterial components 鈥� LPS and E coli K99 鈥� in all 18 aging brains by immunohistochemistry,鈥� said Xinhua Zhan, first author on the paper an associate research professor in the UC Davis Department of Neurology and the MIND Institute. 鈥淜99 was significantly increased in Alzheimer鈥檚 brains compared to controls by Western blot analysis. Also LPS co-localized with amyloid 尾 in amyloid plaques and in blood vessels of Alzheimer鈥檚 brains.鈥�
Researchers have not yet determined if the bacteria are causing Alzheimer's disease or a consequence of it.
Many Gram-negative bacteria are pathogenic, including E. coli, Helicobacter pylori, salmonella, Chlamydophila pneumoniae and Shigella. Researchers have known for some time that infections can increase the risk of Alzheimer鈥檚; however, this is the first time anyone has found increased levels of Gram-negative bacteria antigens in Alzheimer鈥檚 disease brains and bacterial molecules associated with the disease pathology. This research follows previous animal studies in the Sharp lab that showed bacterial LPS plus ischemia/hypoxia can increase amyloid 尾 and produce amyloid plaque-like aggregates.
The study compared 24 gray and white matter samples from patients with the disease 鈥� using Consortium to Establish a Registry for Alzheimer鈥檚 disease criteria 鈥� with 18 samples from people who had shown no evidence of cognitive decline. While LPS and K99 were found in both groups, the prevalence was much higher in the Alzheimer鈥檚 patients. K99 was found in nine of 13 Alzheimer鈥檚 gray-matter samples compared to one of 10 controls by Western blot analysis. Increased K99 levels were also found in Alzheimer鈥檚 disease white matter samples. The story was similar with LPS, which was found in all six samples (three gray and three white matter) but not in the controls by Western blot analysis.
鈥淔inding bacterial molecules in the brain was a surprise, and finding more in the Alzheimer鈥檚 brains was a great surprise,鈥� said Frank Sharp, professor of neurology and senior author on the paper. 鈥淧eople have noted infectious agents in brains. These are the first bacterial molecules that are consistently found in all brains.鈥�
The researchers spent four years validating these results before publishing. In particular, they were concerned about contaminated samples, as LPS is commonly found in many reagents. However, the differentials between the Alzheimer鈥檚 disease samples and controls and the unique localizations of the molecules in Alzheimer鈥檚 brains seem to indicate the team avoided this pitfall.
These findings highlight the need to further investigate how infectious agents impact Alzheimer鈥檚. While discovering LPS and K99 in Alzheimer鈥檚 disease brain samples is a good start, researchers must study the role bacteria may play in the disease pathology. A proven link between bacterial infections and Alzheimer鈥檚 could offer new opportunities to prevent and treat the disease.
鈥淚f LPS is causative, we could immunize against LPS or treat Gram-negative infections more vigorously than we normally do,鈥� Sharp said.
The results will need to be replicated in larger studies to be confirmed. In addition, it鈥檚 not certain Gram-negative bacteria are directly influencing disease progression or are simply a byproduct of other processes.
鈥淲e detected these bacterial components in aging brains,鈥� said Zhan. 鈥淥ur next step will be to work out if this is the cause or the consequence of Alzheimer鈥檚 disease. Do Gram-negative molecules cause the disease or is it that when people get Alzheimer鈥檚 more bacterial molecules get into the brain?鈥�
Other authors included: Boryana Stamova, Lee-Way Jin, Charles DeCarli and Brett Phinney.
The study was funded by NIH/NINDS grant RO1 AG042292 ADC grant AG P30 10129 and grants from The Rotary Coins for Alzheimer鈥檚 Research Trust (CART) (F.R.S) and an Alzheimer鈥檚 Disease Research Award from California Department of Public Health (F.R.S, X.Z.).
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