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By Jamshed Arslan, Pharm. D., PhD.
Gut microbiome modulates various disorders even outside the gut. For example, the microbiome is linked to amyloid-β deposition and the consequent inflammation in Alzheimer’s dementia. Altering gut microbiome through probiotics and/or exercise has been hypothesized to improve memory in Alzheimer’s disease (AD). A multi-continental collaboration of scientists tested this hypothesis on AD mice and found that probiotics and exercise can retard AD progression, at least partly by changing the microbiome.
The researchers used Framelim, a product containing probiotic lysate of Bifidobacterium longum and Lactobacillus acidophilus, multivitamins, and omega 3 fatty acids. Treatment with Framelim with treadmill running was carried out on 3-month old transgenic AD mice for 20 weeks, followed by 2 weeks of memory testing in which Framelim continued. The team used three treatment groups of AD mice: probiotic, exercise, and probiotic-with-exercise. Two untreated groups were used for comparison: transgenic AD and wild-type controls.
As expected, treated mice outperformed untreated ones in hippocampus-dependent cognitive tests. The researchers dissected out the hippocampi and labeled them with microglial activation marker Iba1 and amyloid-beta peptide antibody 6E10. They found a reduced proportion of plaque-covered area with increased microglial accumulation, indicative of microglial clearing of plaques, in all the treated mice relative to untreated AD controls. Interestingly, the exercise group had significantly lower number of plaques compared to all the other AD mice. Exercise group also had improved levels of DNA repair enzyme OGG1 relative to other treatment groups.
A. Immunohistochemical staining of human Alzheimer's disease hippocampus tissue using anti-Amyloid Beta antibody. 6E10 Anti-Amyloid Beta staining of paraffin embedded human hippocampus affected by Alzheimer's disease using the rabbit-chimeric version of 6E10 (NBP2-62566). Antigen retrieval was achieved by microwaving in citrate buffer (pH6), followed by blocking with protein block serum-free buffer. Primary antibody incubation with NBP2-62566 was carried out at 4 ug/ml for 30 minutes. Samples were then incubated with an anti-rabbit IgG HRP secondary antibody for 20 mins followed by DAB (3,3'-diaminobenzidine), and counter-staining with haematoxylin. Staining of amyloid plaques in the parahippocampal gyrus may be observed. Recommended concentration, 2-4 ug/ml. B. AIF-1/Iba1 Antibody [NB100-1028] - Iba-1 staining of microglia in rat hippocampus 40x.
In other words, exercise alone can significantly improve histological and biochemical profile of AD even though it is the combination of exercise and probiotics that improves memory in AD mice. The team moved on to see if these observations were dependent on gut microbiome.
The researchers took fecal samples from mice to determine their microbiome composition. They observed higher Bacteroides thetaiotaomicron levels in AD mice relative to the wild-type. The levels of this bacterium correlated with the results of a cognitive test. Another bacterium Lactobacillus johnsonii was found to be positively correlated with amyloid-β levels in AD mice.
This means that beneficial effects of exercise and/or probiotics in AD can be partly explained by changes in composition of gut bacteria. Future studies are warranted to examine side effects of such microbial alterations.
This study narrows down key bacterial groups in microbiome that are partly responsible for slowing AD progression through exercise and/or probiotic treatment. By showing that amyloid-β levels are not directly correlated with memory performance, this study poses a challenge to most of the experimental treatments that rely solely on reducing amyloid-β aggregates to prevent/cure AD.
Explore Microglia Activation Markers
Jamshed Arslan, Pharm D., PhD.
University of Alabama at Birmingham, School of Medicine
Dr. Arslan studies cell signaling in mitochondrial defects in
C. elegans and transgenic mice.
References
Abraham, Dora, et al. "Exercise and Probiotics Attenuate the Development of Alzheimer's Disease in Transgenic Mice: Role of Microbiome." Experimental Gerontology, vol. 115, 2019, pp. 122–131. https://www.sciencedirect.com/science/article/pii/S0531556518306387?via%3Dihub.
