Mechanisms By Which the Gut Microbiome Influences Amyloid Deposition and Neuroinflammation in the APPswe/ PS1DE9 Mouse Model of Amyloid Beta Amyloidosis

We have generated and characterized mouse models of Alzheimer’s disease that recapitulate the severe amyloid beta-amyloidosis and neuroinflammation evident in the human disease. It has long been assumed that inflammation associated with amyloid deposition reflects the activation of astrocytes and microglia that adopt pro-inflammatory phenotypes,but there is a paucity of information regarding the potential role of peripheral tissues and, more importantly, the gut microbiota in regulating innate immunity that in turn leads to central nervous system(CNS) dysfunction. Indeed, it has become increasingly evident that psychiatric developmental disorders co-exist with common gastrointestinal conditions. Moreover, the microbiome has been implicated in neuroprotection after ischemic lesions, as well as to immunologically mediated neurological conditions such as multiple sclerosis.

Over the past two years, we tested the hypothesis that the composition of the intestinal microbiome might
play a key role in modulating neuroinflammation and amyloid beta deposition. We treated male and femaleAPPSWE/PS1ΔE9 transgenic mice with an antibiotic (ABX) cocktail either postnatally alone, or throughout life, and we reported that while total bacterial abundance was unchanged in either the cecum or feces, there is a distinct perturbation in gut microbial diversity. We demonstrated that amyloid plaque deposition and plaque size are significantly reduced in the brains of male ABX-treated animals, but not in female animals.

Finally, ABX-induced perturbations in gut microbial diversity also paralleled by alterations in the morphology of microglia, scavenger cells that play an important role in removal of amyloid beta plaques.

Having established a strong correlation between alterations in the gut microbiota and decreased levels
of amyloid beta deposition in male APPSWE/PS1ΔE9transgenic mice, there remain several outstanding issues pertinent to the biological mechanism(s) that underlie the observed phenotypes. First, the difference in outcomes between male and female mice is remarkable, and we seek to identify sex-specific genetic changes that could account for the observed differences. Second, we propose to generate APPSWE/PS1ΔE9 mice that are devoid of gut microbes (“germ-free”; GF mice) and evaluate amyloid deposition and neuroinflammation in this model. Third, it is well established that microglia
are considered the primary responders to amyloid beta deposition in the brain and initiate neuroinflammation. We feel it is important to evaluate the genetic changes that occur in these cells as a function of changes in the microbiome. For this purpose, we have obtained a novel transgenic “Ribo-Tag” mouse line from Dr. Jasna Kriz at University of Laval that will allow us to determine the levels of actively translated microglial cell mRNAs and protein products. This new understanding of the role of gut bacteria in modulating amyloid beta-amyloidosis and microglial function in neurodegeneration offers a powerful new approach to identify new targets and/or mechanisms that could be of therapeutic relevance.