Gram-negative bacterial molecules associate with Alzheimer disease pathology

Neurology. 2016 Nov 29;87(22):2324-2332. doi: 10.1212/WNL.0000000000003391. Epub 2016 Oct 26.

Abstract

Objective: We determined whether Gram-negative bacterial molecules are associated with Alzheimer disease (AD) neuropathology given that previous studies demonstrate Gram-negative Escherichia coli bacteria can form extracellular amyloid and Gram-negative bacteria have been reported as the predominant bacteria found in normal human brains.

Methods: Brain samples from gray and white matter were studied from patients with AD (n = 24) and age-matched controls (n = 18). Lipopolysaccharide (LPS) and E coli K99 pili protein were evaluated by Western blots and immunocytochemistry. Human brain samples were assessed for E coli DNA followed by DNA sequencing.

Results: LPS and E coli K99 were detected immunocytochemically in brain parenchyma and vessels in all AD and control brains. K99 levels measured using Western blots were greater in AD compared to control brains (p < 0.01) and K99 was localized to neuron-like cells in AD but not control brains. LPS levels were also greater in AD compared to control brain. LPS colocalized with Aβ1-40/42 in amyloid plaques and with Aβ1-40/42 around vessels in AD brains. DNA sequencing confirmed E coli DNA in human control and AD brains.

Conclusions: E coli K99 and LPS levels were greater in AD compared to control brains. LPS colocalized with Aβ1-40/42 in amyloid plaques and around vessels in AD brain. The data show that Gram-negative bacterial molecules are associated with AD neuropathology. They are consistent with our LPS-ischemia-hypoxia rat model that produces myelin aggregates that colocalize with Aβ and resemble amyloid-like plaques.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / microbiology*
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Blotting, Western
  • Brain / blood supply
  • Brain / metabolism
  • Brain / microbiology*
  • Brain / pathology*
  • DNA, Bacterial / metabolism
  • Escherichia coli
  • Escherichia coli Proteins / metabolism*
  • Female
  • Fluorescent Antibody Technique
  • Gray Matter / blood supply
  • Gray Matter / metabolism
  • Gray Matter / microbiology
  • Gray Matter / pathology
  • Humans
  • Lipopolysaccharides / metabolism*
  • Male
  • Peptide Fragments / metabolism
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / microbiology
  • Plaque, Amyloid / pathology
  • Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • White Matter / metabolism
  • White Matter / microbiology
  • White Matter / pathology

Substances

  • Amyloid beta-Peptides
  • DNA, Bacterial
  • Escherichia coli Proteins
  • Lipopolysaccharides
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)