Probiotic Releasing Angiotensin (1-7) in a Drosophila Model of Alzheimer’s Disease Produces Sex-Specific Effects on Cognitive Function

Article type: Research Article

Authors: Smith, C. Aaron^{a; 1} | Smith, Haddon^{a; 1} | Roberts, Lisa^{b; 2} | Coward, Lori^c | Gorman, Gregory^{a; c} | Verma, Amrisha^d | Li, Qiuhong^d | Buford, Thomas W.^{b; e; *} | Carter, Christy S.^b | Jumbo-Lucioni, Patricia^{a; f; *}

Affiliations: [a] McWhorter School of Pharmacy, Samford University, Birmingham, AL, USA | [b] Department of Medicine; Division of Gerontology, Geriatrics, and Palliative Care, University of Alabama at Birmingham, Birmingham, AL, USA | [c] Pharmaceutical Sciences Research Institute, Samford University, Birmingham, AL, USA | [d] Department of Ophthalmology, College of Medicine, University of Florida Gainesville, FL, USA | [e] Geriatric Research Education and Clinical Center, Birmingham VA Medical Center, Birmingham, AL, USA | [f] Department of Biology, College of Arts and Sciences, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence: [*] Correspondence to: Thomas W. Buford, Department of Medi-cine; Division of Gerontology, Geriatrics, and Palliative Care, University of Alabama at Birmingham, Birmingham, AL, USA. Tel.: +1 205 975 9042; E-mail: twbuford@uabmc.edu and Patricia Jumbo-Lucioni, McWhorter School of Pharmacy, Samford University, Birmingham, AL, USA. Tel.: +1 205 726 4170; E-mail: pjumbolu@samford.edu.

Note: [1] These authors contributed equally to this work.

Note: [2] Present address: College of Health and Rehabilitation Sciences, Boston University, Boston, MA, USA.

Abstract: Background: While extensive research on the brain has failed to identify effective therapies, using probiotics to target the gut microbiome has shown therapeutic potential in Alzheimer’s disease (AD). Genetically modified probiotics (GMP) are a promising strategy to deliver key therapeutic peptides with high efficacy and tissue specificity. Angiotensin (Ang)-(1-7) levels inversely correlate to AD severity, but its administration is challenging. Our group has successfully established a GMP-based method of Ang-(1-7) delivery. Objective: Since Drosophila represents an excellent model to study the effect of probiotics on complex disorders in a high throughput manner, we tested whether oral supplementation with Lactobacillus paracasei releasing Ang-(1-7) (LP-A) delays memory loss in a Drosophila AD model. Methods: Flies overexpressing the human amyloid-β protein precursor and its β-site cleaving enzyme in neurons were randomized to receive four 24-h doses of Lactobacillus paracasei alone (LP), LP-A or sucrose over 14 days. Memory was assessed via an aversive phototaxic suppression assay. Results: Optimal dilution,1:2, was determined based on palatability. LP-A improved memory in trained AD males but worsened cognition in AD females. LP-supplementation experiments confirmed that Ang-(1-7) conferred additional cognitive benefits in males and was responsible for the deleterious cognitive effects in females. Sex-specific differences in the levels of angiotensin peptides and differential activation of the kynurenine pathway of tryptophan metabolism in response to supplementation may underlie this male-only therapeutic response. Conclusion: In summary, LP-A ameliorated the memory deficits of a Drosophila AD model, but effects were sex-specific. Dosage optimization may be required to address this differential response.

Keywords: Alzheimer’s disease, angiotensin (1-7), probiotic, Lactobacillus, tryptophan

DOI: 10.3233/JAD-210464

Journal: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1205-1217, 2022