Oral administration of Pantoea agglomerans-derived lipopolysaccharide prevents metabolic dysfunction and Alzheimer's disease-related memory loss in senescence-accelerated prone 8 (SAMP8) mice fed a high-fat diet

PLoS One. 2018 Jun 1;13(6):e0198493. doi: 10.1371/journal.pone.0198493. eCollection 2018.

Abstract

The pathogenesis of Alzheimer's disease (AD) remains unclear, but an imbalance between the production and clearance of amyloid-β (Aβ) peptides is known to play a critical role in AD progression. A promising preventative approach is to enhance the normal Aβ clearance activity of brain phagocytes such as microglia. In mice, the intraperitoneal injection of Toll-like receptor 4 agonist was shown to enhance Aβ clearance and exhibit a preventative effect on AD-related pathology. Our previous clinical study demonstrated that orally administered Pantoea agglomerans-derived lipopolysaccharide (LPSp) exhibited an LDL (low-density lipoprotein)-lowering effect in human volunteers with hyperlipidemia, a known risk factor for AD. In vitro studies have shown that LPSp treatment increases Aβ phagocytosis by microglial cells; however it is still unclear whether orally administered LPSp exhibits a preventive effect on AD progression. We show here that in senescence-accelerated prone 8 (SAMP8) mice fed a high-fat diet, oral administration of LPSp at 0.3 or 1 mg/kg body weight·day for 18 weeks significantly improved glucose metabolism and lipid profiles. The LPSp treatment also reduced pro-inflammatory cytokine expression and oxidative-burst activity in the peripheral blood. Moreover, LPSp significantly reduced brain Aβ burden and memory impairment as seen in the water maze test, although we could not confirm a significant enhancement of Aβ phagocytosis in microglia isolated from the brains after treatment. Taken together, our results show that LPSp holds promise as a preventative therapy for AD or AD-related diseases induced by impairment of metabolic functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Alzheimer Disease / complications
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / metabolism
  • Cytokines / metabolism
  • Diet, High-Fat*
  • Disease Models, Animal
  • Glucose / metabolism
  • Glycated Hemoglobin A / analysis
  • Lipid Metabolism / drug effects
  • Lipopolysaccharides / pharmacology
  • Lipopolysaccharides / therapeutic use*
  • Male
  • Maze Learning
  • Memory Disorders / etiology
  • Memory Disorders / prevention & control*
  • Metabolic Diseases / pathology
  • Metabolic Diseases / prevention & control*
  • Mice
  • Microglia / cytology
  • Microglia / metabolism
  • Pantoea / metabolism*
  • Phagocytosis

Substances

  • Amyloid beta-Peptides
  • Cytokines
  • Glycated Hemoglobin A
  • Lipopolysaccharides
  • Glucose

Grant support

This work was supported by the Council for Science, Technology and Innovation (CSTI), Cross-ministerial Strategic Innovation Promotion Program (SIP) and‘Technologies for creating next-generation agriculture, forestry and fisheries’ (funding agency: Bio-oriented Technology Research Advancement Institution, NARO). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CK is employed by Macrophi Inc. The funder provided support in the form of salaries for author [CK], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. KK, HT and TM are employed by Hamamatsu Photonics K.K. The funder provided support in the form of salaries for authors [KK, HT and TM],but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.