Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Rescue Memory Defects in Drosophila-Expressing Alzheimer's Disease-Related Transgenes Independently of the Canonical Renin Angiotensin System.

Alzheimer's disease (AD) is a degenerative disorder that causes progressive memory and cognitive decline. Recently, studies have reported that inhibitors of the mammalian renin angiotensin system (RAS) result in a significant reduction in the incidence and progression of AD by unknown mechanisms. Here, we used a genetic and pharmacological approach to evaluate the beneficial effects of angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) in Drosophila expressing AD-related transgenes. Importantly, while ACE orthologs have been identified in Drosophila, other RAS components are not conserved. We show that captopril, an ACE-I, and losartan, an ARB, can suppress a rough eye phenotype and brain cell death in flies expressing a mutant human C99 transgene. Captopril also significantly rescues memory defects in these flies. Similarly, both drugs reduce cell death in Drosophila expressing human Aß42 and losartan significantly rescues memory deficits. However, neither drug affects production, accumulation or clearance of Aß42 Importantly, neither drug rescued brain cell death in Drosophila expressing human Tau, suggesting that RAS inhibitors specifically target the amyloid pathway. Of note, we also observed reduced cell death and a complete rescue of memory deficits when we crossed a null mutation in Drosophila Acer into each transgenic line demonstrating that the target of captopril in Drosophila is Acer. Together, these studies demonstrate that captopril and losartan are able to modulate AD related phenotypes in the absence of the canonical RAS pathway and suggest that both drugs have additional targets that can be identified in Drosophila.

Effects of Bifidobacterium bifidum in Mice Infected with Citrobacter rodentium.

In vitro and in vivo studies suggest that selected Bifidobacterium bifidum strains sustain intestinal homeostasis. This study aimed to examine whether the administration of B. bifidum MIMBb75 (BB75) attenuates Citrobacter rodentium infection, a murine model for enteric infection and inflammatory bowel disease in humans. C57Bl6/J mice were randomized to receive BB75 daily starting before or after C. rodentium infection. BB75 load and infection kinetics were monitored. On day 10 post-infection (p.i.), histological parameters of the large intestine were assessed. Barrier integrity was evaluated by pathogen translocation to secondary organs and in vivo permeability test. Fecal C. rodentium load peaked at 1010 CFU/g at day 10 p.i., with clearance at day 24 p.i., regardless of probiotic treatment. BB75 administration resulted in 107 cells/g of feces with no effect of timing of administration. BB75 treatment did not attenuate C. rodentium-induced crypt hyperplasia nor inflammation. C. rodentium and BB75 can co-exist in the gut with no mutual displacement. However, BB75 cannot counteract C. rodentium pathology. Our findings provide insight for the understanding of probiotics behavior and their clinical relevance in intestinal inflammation.