Gut microbiome perturbations influence brain amyloidosis only in the presence of microglia in APPPS1- 21 mice
Dodiya, Hemraj B.; Lutz, Holy; Weigle, Ian; Roman‐santiago, Carlos; Patel, Priyam; Olszewski, Monica; Zhang, Can; Zhang, Xiaoqiong; Schipma, Matthew John; Tanzi, Rudolph E.; Gilbert, Jack A.; Sisodia, Sangram S.
2020-12
Citation
Dodiya, Hemraj B.; Lutz, Holy; Weigle, Ian; Roman‐santiago, Carlos ; Patel, Priyam; Olszewski, Monica; Zhang, Can; Zhang, Xiaoqiong; Schipma, Matthew John; Tanzi, Rudolph E.; Gilbert, Jack A.; Sisodia, Sangram S. (2020). "Gut microbiome perturbations influence brain amyloidosis only in the presence of microglia in APPPS1- 21 mice." Alzheimer’s & Dementia 16: n/a-n/a.
Abstract
BackgroundIn prior efforts, we demonstrated reduced amyloidosis and altered microgliosis in long- term antibiotics (abx)- treated APPPS1- 21 male mice. Restoration of the gut microbiome into abx- treated male mice by fecal microbiota transfer (FMT) established a causality between the gut microbiome and amyloidosis. We have used FMT studies using our current short- term abx APPPS1- 21 mice to evaluate the microbiome- microglia- amyloidosis axis.MethodShort- term, postnatal abx (4mg/ml Kanamycin, 0.35mg/ml Gentamicin, 8500U/ml Colistin, 2.15mg/ml Metronidazole, 0.45mg/ml Vancomycin: post- natal day 14 to day 21) was performed. To establish causality, we performed FMT (200µl of 5mg/ml fecal slurry daily gavage) into abx- treated APPPS1- 21 male mice. Pathogenicity of the gut microbiome in WT or Tg mice were confirmed using age- matched FMT from WT and Tg controls into abx- treated male mice. We performed total RNAseq transcriptome analysis to evaluate potential mechanism(s). The role of microglial cells were evaluated in PLX6522 (CSF- 1 receptor inhibitor)- treated FMT- transplanted abx- treated APPPS1- 21 male mice. Nine weeks old GF APPPS1- 21 were used to characterize the amyloidosis and glial cells in both genders.ResultAn early life abx treatment resulted in gut microbiota changes in a sex- dependent manner. Only male mice showed reduced amyloidosis and altered microglial phenotypes. Age matched Tg FMT or WT FMT resulted in higher amyloidosis in abx- treated male mice. RNAseq analysis of total cortical RNA showed significantly different mRNA levels that occurred in a sex- specific manner and changes in abx- treated male mice were restored with FMT. GO term analysis showed gliogenesis and microglia development as significantly altered pathways in abx- treated male group only. To confirm the exact role of the microglia in this model, we employed PLX6522 in FMT- treated ABX- male mice. Microglia depletion did not result in an FMT- dependent increase in amyloidosis in abx- treated male mice. Finally, germ- free APPPS1- 21 mice showed reduced amyloidosis that occurs in a sex- specific manner.ConclusionFrom GF APPPS1- 21 and FMT- treated abx- male APPPS1- 21 studies, we conclude that gut microbiome plays a critical role in modulating amyloidosis in APPPS1- 21 mice. Furthermore, microglia mediates the effects of early life gut microbiota perturbations, which results in altered amyloidosis in APPPS1- 21 male mice.Publisher
Wiley Periodicals, Inc.
ISSN
1552-5260 1552-5279
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