Alzheimer’s Disease: Protective Effects of Mycobacterium vaccae, a Soil-Derived Mycobacterium with Anti-Inflammatory and Anti-Tubercular Properties, on the Proteomic Profiles of Plasma and Cerebrospinal Fluid in Rats

Article type: Research Article

Authors: Loupy, Kelsey M.^a | Lee, Thomas^b | Zambrano, Cristian A.^a | Elsayed, Ahmed I.^a | D’Angelo, Heather M.^c | Fonken, Laura K.^d | Frank, Matthew G.^{c; e} | Maier, Steven F.^{c; e} | Lowry, Christopher A.^{a; e; f; g; h; i; j; *}

Affiliations: [a] Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA | [b] Central Analytical Laboratory and Mass Spectrometry Facility, Department of Biochemistry, University of Colorado Boulder, Boulder, CO, USA | [c] Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA | [d] Division of Pharmacology and Toxicology, University of Texas at Austin, Austin, TX, USA | [e] Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA | [f] Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, USA | [g] Department of Physical Medicine and Rehabilitation and Center for Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, CO, USA | [h] Veterans Health Administration, Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Rocky Mountain Regional Veterans Affairs Medical Center (RMRVAMC), Aurora, CO, USA | [i] Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, CO, USA | [j] Senior Fellow, inVIVO Planetary Health, of the Worldwide Universities Network (WUN), West New York, NJ, USA

Correspondence: [*] Correspondence to: Christopher A. Lowry, Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309-0354, USA. Tel.: +1 303 492 6029; E-mail: [email protected].

Abstract: Background:Alzheimer’s disease (AD) is an inflammatory neurodegenerative disease that may be associated with prior bacterial infections. Microbial “old friends” can suppress exaggerated inflammation in response to disease-causing infections or increase clearance of pathogens such as Mycobacterium tuberculosis, which causes tuberculosis (TB). One such “old friend” is Mycobacterium vaccae NCTC 11659, a soil-derived bacterium that has been proposed either as a vaccine for prevention of TB, or as immunotherapy for the treatment of TB when used alongside first line anti-TB drug treatment. Objective:The goal of this study was to use a hypothesis generating approach to explore the effects of M. vaccae on physiological changes in the plasma and cerebrospinal fluid (CSF). Methods:Liquid chromatography-tandem mass spectrometry-based proteomics were performed in plasma and CSF of adult male rats after immunization with a heat-killed preparation of M. vaccae NCTC 11659 or borate-buffered saline vehicle. Gene enrichment analysis and analysis of protein-protein interactions were performed to integrate physiological network changes in plasma and CSF. We used RT-qPCR to assess immune and metabolic gene expression changes in the hippocampus. Results:In both plasma and CSF, immunization with M. vaccae increased proteins associated with immune activation and downregulated proteins corresponding to lipid (including phospholipid and cholesterol) metabolism. Immunization with M. vaccae also increased hippocampal expression of interleukin-4 (IL-4) mRNA, implicating anti-inflammatory effects in the central nervous system. Conclusion:M. vaccae alters host immune activity and lipid metabolism. These data are consistent with the hypothesis that microbe-host interactions may protect against possible infection-induced, inflammation-related cognitive impairments.

Keywords: Alzheimer’s disease, ApoA-I, ApoC-II, cerebrospinal fluid, inflammation, lipid metabolism, mycobacteria, neurodegenerative disorder, neuroimmunomodulation, proteomics

DOI: 10.3233/JAD-200568

Journal: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 965-987, 2020