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Characterizing the Effect of Chronic Copper Exposure on Neuropathology and Induction of Gut Microbiome Dysbiosis in an APP Knock-In Model of Alzheimer's Disease

Creative Commons 'BY' version 4.0 license

Chronic exposure to copper is a putative environmental risk factor for AD. Although copper is an essential metal, environmental exposure to its inorganic cupric form (Cu2+) may exert toxicity. However, exact neurotoxic mechanisms of action of copper, and its contribution to AD neuropathology remain largely unelucidated. Copper is a natural antimicrobial agent, and here, we investigate its impact of copper exposure on the gut microbiome and integrity as well as effects on cognition and AD pathology. Recent studies implicate gut dysbiosis in the onset and progression of AD in both humans and animal models. We believe that chronic exposure to environmentally relevant dose of copper through drinking water will reduce richness and diversity of the gut microbiota in both WT and hAPPNL-G-F knock-in (APP-KI) mice. Thus, we hypothesize that this copper-induced dysbiosis may perturb host metabolism and inflammatory homeostasis to contribute to AD neuropathology. In this dissertation, male and female APP-KI and wildtype C57BL/6J mice were exposed to 1.3 ppm CuCl2 in drinking water ad-libitum for 3(pilot study) and 9(chronic study) months. The present studies use a host of behavioral, immunohistochemical, biochemical and microbial analyses to investigate the effect of copper on microbiota, amyloidosis, neuroinflammation and cognition in AD mice.

In our pilot study, we discovered that while there were no significant changes in AD neuropathology or inflammatory status in WT or APP-KI mice, we observed that WT mice microbiota were resilient to the effects of copper administration. However, beginning 1 month after initiation of exposure, APP-KI mice developed a significantly different microbial composition according to the Bray Curtis -diversity. This was largely driven by a decrease in Firmicutes, and specifically in the genus Allobaculum and an increase in the phylum Bacteroidetes, specifically in the genus S24-7. These changes mirror some of the changes observed in studies in other AD mouse models and AD patients.

In our chronic study, spanning from after weaning and until the mice were 10 months, old, we discovered no significant changes in cognition and a mild change in the cytokine profile of AD mice, with a reduction of IL-4 in plasma, following copper administration. With this longer treatment paradigm, we did observe increased in amyloidosis, both dense core and diffuse plaques, with copper treatment. Further, along with evidence that plaque-associated microglia are of a diseased phenotype, the amount of these microglia was significantly increased with copper treatment indicating that copper perturbs neuroinflammation. In the gut microbiota, we observe unexpected results. Copper directs the developmental trajectory of WT mice but with time the microbiota of AD mice is not changed much. This may indicate differing windows of susceptibility to copper exposure between the genotypes of mice and between pilot study and the chronic study paradigms.

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