Michael Woolley

 Introduction. Alzheimer disease (AD) is the leading cause of dementia in the United States¹. As many as 5 million new cases are diagnosed each year, and that number is expected to increase as the Baby Boomer generation ages². Despite years of research in search of effective treatments, nothing has yet been developed to prevent or slow progress of the disease^3,4. Continued research efforts have led to the emergence of the hypothesis that inflammation may play an essential role in the etiology of AD and may offer novel therapeutic targets^1,4. At the same time, researchers noticed a link between AD and gut dysbiosis^5-11. Work is currently underway to understand this link and the mechanisms that might be at play. One such study examined the effects of inducing gut dysbiosis in a Drosophila model of AD¹¹. Methods. Researchers used a transgenic Drosophila strain that ectopically expresses amyloid-β in their brain. They infected the flies with a non- pathogenic enterobacteria (Ecc15). They examined gross phenotypic changes in behavior and lifespan, in addition to immunohistochemical staining for markers of inflammation and apoptosis. Results. The researchers found that infected transgenic flies showed significantly more neurodegeneration compared to the non-transgenic controls¹¹. Immunostaining revealed significant increases in apoptotic and inflammatory markers in the infected transgenic flies¹¹. In addition to the increased neuronal loss, infected transgenic flies displayed decreased locomotor activity and lifespan compared to controls¹¹. Further examination revealed that these alterations were being mediated by upregulation of TNF eiger signaling in the infected transgenic flies¹¹. Blocking eiger signaling resulted in significant decreases in neuronal loss and increases in lifespan¹¹. Ecc15 infection was also shown to lead to increased hemocyte recruitment to the CNS in the infected transgenic flies¹¹. Infected transgenic flies genetic depleted of hemocytes show significantly decreased neurodegeneration and markedly improved survival, strongly indicating that hemocyte activity in the CNS is an important factor in neuronal loss¹¹. Conclusions. This study, though conducted using a Drosophila model of human disease and only adding a single bacterial species to alter the gut microbiome, offers evidence that there is an important gut-brain interplay at work in AD. A better understanding of the mechanisms involved may open the doors to novel therapeutic targets and the hope of better treatments for AD.

1. Wyss-Coray, T. and Rogers, Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med, 2012. 2(1): p. a006346.
2. Onojighofia Tobore, T., On the Etiopathogenesis and Pathophysiology of Alzheimer’s Disease: A Comprehensive Theoretical Review. J Alzheimers Dis,
3. Bondi, M.W., E.C. Edmonds, and D.P. Salmon, Alzheimer’s Disease: Past, Present, and Future. J Int Neuropsychol Soc, 2017. 23(9-10): p. 818-831.
4. McCaulley, M.E. and K.A. Grush, Alzheimer’s Disease: Exploring the Role of Inflammation and Implications for Treatment. Int J Alzheimers Dis, 2015. 2015: p.
5. Hill, J.M., et al., The gastrointestinal tract microbiome and potential link to Alzheimer’s disease. Front Neurol, 2014. 5: p.
6. Junges, V.M., et al., Crosstalk between Gut Microbiota and Central Nervous System: A Focus on Alzheimer’s Disease. Curr Alzheimer Res, 2018. 15(13): p. 1179-1190.
7. Kohler, C.A., et al., The Gut-Brain Axis, Including the Microbiome, Leaky Gut and Bacterial Translocation: Mechanisms and Pathophysiological Role in Alzheimer’s Disease. Curr Pharm Des, 2016. 22(40): p. 6152-6166.
8. Peng, W., et al., Association of gut microbiota composition and function with a senescence-accelerated mouse model of Alzheimer’s Disease using 16S rRNA gene and metagenomic sequencing analysis. Aging (Albany NY), 2018. 10(12): p. 4054-4065.
9. Ticinesi, A., et al., Gut microbiota, cognitive frailty and dementia in older individuals: a systematic review. Clin Interv Aging, 2018. 13: p. 1497-1511.
10. Vogt, N.M., et al., Gut microbiome alterations in Alzheimer’s disease. Sci Rep, 2017. 7(1): p.
11. Wu, S.C., et al., Intestinal microbial dysbiosis aggravates the progression of Alzheimer’s disease in Drosophila. Nat Commun, 2017. 8(1): p.