Abstract
Alzheimer's disease (AD), a progressive neurodegenerative disorder, lacks preclinical diagnostic biomarkers and therapeutic drugs. Thus, earlier intervention in AD is a top priority. Studies have shown that the gut microbiota influences central nervous system disorders and that prebiotics can improve the cognition of hosts with AD, but these effects are not well understood. Preliminary research has shown that oligosaccharides from Morinda officinalis (OMO) are a useful prebiotic and cause substantial memory improvements in animal models of AD; however, the mechanism is still unclear. Therefore, this study was conducted to investigate whether OMO are clinically effective in alleviating AD by improving gut microbiota. OMO were administered to APP/PS1 transgenic mice, and potential clinical biomarkers of AD were identified with metabolomics and bioinformatics. Behavioral experiments demonstrated that OMO significantly ameliorated the memory of the AD animal model. Histological changes indicated that OMO ameliorated brain tissue swelling and neuronal apoptosis and downregulated the expression of the intracellular AD marker Aβ1−42. 16S rRNA sequencing analyses indicated that OMO maintained the diversity and stability of the microbial community. The data also indicated that OMO are an efficacious prebiotic in an animal model of AD, regulating the composition and metabolism of the gut microbiota. A serum metabolomics assay was performed using UHPLC-LTQ Orbitrap mass spectrometry to delineate the metabolic changes and potential early biomarkers in APP/PS1 transgenic mice. Multivariate statistical analysis showed that 14 metabolites were significantly upregulated, and 8 metabolites were downregulated in the model animals compared to the normal controls. Thus, key metabolites represent early indicators of the development of AD. Overall, we report a drug and signaling pathway with therapeutic potential, including proteins associated with cognitive deficits in normal mice or gene mutations that cause AD.
Highlights
As an irreversible neurodegenerative disease that causes cognitive deficits, Alzheimer’s disease (AD) accounts for 60–80% of all types of dementia [1]
Mice that received a low dose of oligosaccharides from Morinda officinalis (OMO) displayed an incubation time (IT) of 86.49 ± 11.64 s, while mice receiving the high dose exhibited an IT of 82.06 ± 19.44 s on the 1st day; both values were noticeably different (p < 0.01) from the model group (113.75 ± 16.11)
On the 4th day, the IT of mice treated with a low dose of OMO was reduced to 37.19 ± 5.36 s, while the IT of the highdose group decreased to 28.27 ± 3.96 s, both of which differed remarkably from APP/PS1 mice (56.29 ± 9.69 s, p < 0.01, Figure 1B)
Summary
As an irreversible neurodegenerative disease that causes cognitive deficits, Alzheimer’s disease (AD) accounts for 60–80% of all types of dementia [1]. Some pathological features of AD, including cerebral atrophy, amyloid generation, altered gene expression, altered immune reactions, and cognitive deficits, have recently been linked to microbe infections [6,7,8,9,10]. The brain and gut interact and modulate each other [11], and microbes in the gastrointestinal tract (GIT) are postulated to participate in AD development [12,13,14], our understanding of the development and pathology of AD is insufficient and changing. Metabolomics has been used to identify metabolites and determine the expression of related genes in whole organisms, and it has recently been used in a wide range of applications in the clinic. The gut microbiota and their metabolites influence the host metabolism [25]. The roles of the gut microbiota and serum metabolites in AD are unclear
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