Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes

• DOI: 10.1084/jem.20182386
• Publication Date: 2019-05-16T18:55:14Z
• Authors: Hemraj B. Dodiya; Thomas Kuntz; Shabana M. Shaik; Caroline Baufeld; Jeffrey Leibowitz; Xulun Zhang; Neil Gottel; Xiaoqiong Zhang; Oleg Butovsky; Jack A. Gilbert; Sangram S. Sisodia
• Keywords: Male; Aging; Amyloid; Immunology; Plaque, Amyloid; Neurodegenerative; Alzheimer's Disease; Amyloid Neuropathies; Medical and Health Sciences; Amyloid beta-Protein Precursor; Mice; 03 medical and health sciences; Sex Factors; Genetics; Acquired Cognitive Impairment; 2.1 Biological and endogenous factors; Animals; Aetiology; Research Articles; Plaque; Brain Diseases; 0303 health sciences; Animal; Neurosciences; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Fecal Microbiota Transplantation; Brain Disorders; Anti-Bacterial Agents; Gastrointestinal Microbiome; Disease Models, Animal; Disease Models; Dementia; Female; Microglia

We demonstrated that an antibiotic cocktail (ABX)-perturbed gut microbiome is associated with reduced amyloid-β (Aβ) plaque pathology and astrogliosis in the male amyloid precursor protein (APP)SWE/presenilin 1 (PS1)ΔE9 transgenic model of Aβ amyloidosis. We now show that in an independent, aggressive APPSWE/PS1L166P (APPPS1-21) mouse model of Aβ amyloidosis, an ABX-perturbed gut microbiome is associated with a reduction in Aβ pathology and alterations in microglial morphology, thus establishing the generality of the phenomenon. Most importantly, these latter alterations occur only in brains of male mice, not in the brains of female mice. Furthermore, ABX treatment lead to alterations in levels of selected microglial expressed transcripts indicative of the “M0” homeostatic state in male but not in female mice. Finally, we found that transplants of fecal microbiota from age-matched APPPS1-21 male mice into ABX-treated APPPS1-21 male restores the gut microbiome and partially restores Aβ pathology and microglial morphology, thus demonstrating a causal role of the microbiome in the modulation of Aβ amyloidosis and microglial physiology in mouse models of Aβ amyloidosis.