Brain bioavailable microbiome derived flavonoid metabolite attenuates neuroinflammation in C9orf72 associated frontotemporal dementia: Nonhuman/Lead optimization studies. (7th December 2020)

• Record Type: Journal Article
• Authors: Iqbal, Umar Haris; Smith, Chad; Trageser, Kyle J.; Pasinetti, Giulio Maria
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 9
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.046035
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Familial frontotemporal dementia (FTD) has been associated with mutations in the G4 C2 promoter of C9orf72 leading to production of dipeptide protein repeats (DPRs), the most neurotoxic being Glycine‐Arginine (GR). Previous studies have found a parallel relationship with the accumulation of DPRs and a neuroinflammatory response. Specifically, studies have determined microglia proliferation and persistent activation plays a role in disease progression and neurodegeneration. The current study investigated the effect of the bioavailable microbiome derived flavonol metabolite, 3‐hydroxybenzoic acid (3‐HBA) (Wang D. et al, 2015), on microglia morphology and proliferation in mice harboring the AAV9‐GFP(GR)100 virus in the brain recapitulating FTD type neuropathology and behavior. Method: Mice were divided into three groups: GFP control, GR100, and GR100 with 3‐HBA. The GFP control group was transfected with AAV9‐GFP through intra‐cerebroventricular injection, whereas the other two groups were transfected with AAV9‐GFP(GR)100 . The virus was administered on postnatal day 0, and the treatment of 3‐HBA began on day 28 for a period of 10 weeks. Immunofluorescence staining of microglia was performed on sections spanning the prelimbic/infralimbic cortex, primary somatosensory cortex (S1), and the hippocampus in order to stereologically quantify microglia proliferation and to reconstruct the microglia in 3D using the imaging software Imaris. Result: Stereological counting determined an increase in microglia density of approximately 40% (p < 0.05) in the S1 of mice transfected with AAV9‐GFP(GR)100 . In addition, there was approximately 30% (p < 0.0001) reduction in S1, and hippocampal volume in groups transfected with AAV9‐GFP(GR)100 . 3D reconstruction and Sholl analysis determined a change in microglia morphology from a surveilling state, as seen in the GFP control group, to that of activation characterized by increased branching closer to the soma, as observed in the GR100 group. This increased complexity/activation was found to be attenuated with the administration of 3‐HBA which was associated with a significant reduction in branch complexity compared to both the control and GR100 group. Conclusion: This study identifies a novel microbiome derived polyphenol that displayed potential in attenuating microglia activation, and hence reducing the neuroinflammatory response in FTD.