@article{TEXTUAL,
      recid = {6657},
      author = {Chandra, Sidhanth and Di Meco, Antonio and Dodiya, Hemraj  B. and Popovic, Jelena and Cuddy, Leah K. and Weigle, Ian  Q. and Zhang, Xiaoqiong and Sadleir, Katherine and Sisodia,  Sangram S. and Vassar, Robert},
      title = {The gut microbiome regulates astrocyte reaction to Aβ  amyloidosis through microglial dependent and independent  mechanisms},
      journal = {Molecular Neurodegeneration},
      address = {2023-07-06},
      number = {TEXTUAL},
      abstract = {&lt;p&gt;Background: Previous studies show that  antibiotic-mediated (abx) alteration of the gut microbiome  (GMB) results in a reduction of amyloid beta (Aβ) plaques  and proinflammatory microglial phenotype in male APPPS1-21  mice. However, the effect of GMB perturbation on astrocyte  phenotypes and microglial-astrocyte communication in the  context of amyloidosis has not been examined.&lt;/p&gt;  &lt;p&gt;Methods: To study whether the GMB modulates astrocyte  phenotype in the context of amyloidosis, APPPS1-21 male and  female mice were treated with broad-spectrum abx leading to  GMB perturbation. GFAP + astrocytes, plaque-associated  astrocytes (PAA), PAA morphological parameters, and  astrocyte complement component C3 levels were quantified  using a combination of immunohistochemistry,  immunoblotting, widefield microscopy, and confocal  microscopy. Furthermore, these same astrocyte phenotypes  were assessed in abx-treated APPPS1-21 male mice that  received either fecal matter transplant (FMT) from  untreated APPPS1-21 male donors to restore their microbiome  or vehicle control. To assess complete absence of the GMB  on astrocyte phenotypes, the same astrocyte phenotypes were  quantified in APPPS1-21 male mice raised in germ-free (GF)  or specific-pathogen free conditions (SPF). Lastly, we  assessed whether microglia are necessary for abx-induced  astrocyte phenotypes by depleting microglia in APPPS1-21  male mice via treatment with a colony-stimulating factor 1  receptor (CSF1R) inhibitor (PLX5622) and vehicle control or  PLX5622 and abx.&lt;/p&gt; &lt;p&gt;Results: Herein, we demonstrate  that postnatal treatment of male APPPS1-21 mice with  broad-spectrum abx leading to GMB perturbation reduces GFAP  + reactive astrocytes and PAAs, suggesting that the GMB  plays a role in regulating reactive astrocyte induction and  recruitment to Aβ plaques. Additionally, we show that  compared to controls, PAAs in abx-treated male APPPS1-21  mice exhibit an altered morphology with increased number  and length of processes and reduced astrocytic complement  C3, consistent with a homeostatic phenotype. GFAP +  astrocyte reduction, PAA reduction, astrocyte morphological  changes, and C3 levels are restored when abx-treated mice  are subject to FMT from untreated APPPS1-21 male donor  mice. Next, we found that APPPS1-21 male mice raised in GF  conditions have similar astrocyte phenotypes as abx-treated  male APPPS1-21 male mice. Correlational analysis revealed  that pathogenic bacteria depleted by abx correlate with  GFAP + astrocytosis, PAAs, and astrocyte morphological  changes. Finally, we determined that abx-mediated reduction  in GFAP + astrocytosis, PAAs, and astrocytic C3 expression  is independent of microglia. However, abx-induced astrocyte  morphological alterations are dependent on the presence of  microglia, suggesting that there is both microglial  independent and dependent GMB control of reactive astrocyte  phenotypes.&lt;/p&gt; &lt;p&gt;Conclusions: We show for the first time,  in the context of amyloidosis, that the GMB plays an  important role in controlling reactive astrocyte induction,  morphology, and astrocyte recruitment to Aβ plaques. GMB  regulation of these astrocytic phenotypes is both  independent and dependent on microglia.&lt;/p&gt;},
      url = {http://knowledge.uchicago.edu/record/6657},
}