Trimethylamine N-Oxide Reduces Neurite Density and Plaque Intensity in a Murine Model of Alzheimer’s Disease

Article type: Research Article

Authors: Zarbock, Katie R.^{a; b} | Han, Jessica H.^{a; c} | Singh, Ajay P.^d | Thomas, Sydney P.^c | Bendlin, Barbara B.^{e; f} | Denu, John M.^c | Yu, John-Paul J.^d | Rey, Federico E.^{a; *} | Ulland, Tyler K.^{b; *}

Affiliations: [a] Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA | [b] Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA | [c] Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI, USA | [d] Department of Radiology, Division of Neuroradiology, University of Wisconsin-Madison, Madison, WI, USA | [e] Department of Medicine, Division of Geriatrics and Gerontology, University of Wisconsin-Madison, Madison, WI, USA | [f] Wisconsin Alzheimer’s Disease Research Center, Madison, WI, USA

Correspondence: [*] Correspondence to: Dr. Federico E. Rey, Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA. Tel.: +1 608 890 2046; E-mail: [email protected] and Dr. Tyler K. Ulland, Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA. Tel.: +1 608 263 0832; E-mail: [email protected].

Abstract: Background:Alzheimer’s disease (AD) is the most common aging-associated neurodegenerative disease; nevertheless, the etiology and progression of the disease is still incompletely understood. We have previously shown that the microbially-derived metabolite trimethylamine N-oxide (TMAO) is elevated in the cerebrospinal fluid (CSF) of individuals with cognitive impairment due to AD and positively correlates with increases in CSF biomarkers for tangle, plaque, and neuronal pathology. Objective:We assessed the direct impact of TMAO on AD progression. Methods:To do so, transgenic 5XFAD mice were supplemented with TMAO for 12 weeks. Neurite density was assessed through quantitative brain microstructure imaging with neurite orientation dispersion and density imaging magnetic resonance imaging (MRI). Label-free, quantitative proteomics was performed on cortex lysates from TMAO-treated and untreated animals. Amyloid-β plaques, astrocytes, and microglia were assessed by fluorescent immunohistochemistry and synaptic protein expression was quantified via western blot. Results:Oral TMAO administration resulted in significantly reduced neurite density in several regions of the brain. Amyloid-β plaque mean intensity was reduced, while plaque count and size remained unaltered. Proteomics analysis revealed that TMAO treatment impacted the expression of 30 proteins (1.5-fold cut-off) in 5XFAD mice, including proteins known to influence neuronal health and amyloid-β precursor protein processing. TMAO treatment did not alter astrocyte and microglial response nor cortical synaptic protein expression. Conclusion:These data suggest that elevated plasma TMAO impacts AD pathology via reductions in neurite density.

Keywords: Alzheimer’s disease, neurites, trimethylamine N-oxide

DOI: 10.3233/JAD-220413

Journal: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 585-597, 2022