Mannan oligosaccharide attenuates cognitive and behavioral disorders in the 5xFAD Alzheimer's disease mouse model via regulating the gut microbiota-brain axis
Graphical abstract
Introduction
Alzheimer's disease (AD), as a neurodegenerative disease, seriously threatens about 6% of people 65 years and older (Burns and Iliffe, 2009). Around 50 million people worldwide are suffering from dementia, and the total number of patients is expected to reach 131 million by 2050 (Tiwari et al., 2019, Van Cauwenberghe et al., 2016). AD patients suffer from memory loss and cognitive disorder accompanied by neuropsychiatric symptoms accelerating cognition impairment, such as anxiety and depression. (Ferretti et al., 2001, Ismail et al., 2016, Pietrzak et al., 2015). Nevertheless, the mechanisms of AD pathogenesis have remained largely abstruse. The main pathological changes are characterized by neurofibrillary tangles with excessive hyperphosphorylated Tau protein in nerve cells and senile plaques accumulated of aberrant extracellular amyloid-β (Aβ) (Arriagada et al., 1992, Janus et al., 2000). The accumulation of Aβ triggers inflammatory responses and oxidative stress in the brain, which are the main risk factors for dementia-related neurodegeneration (Butterfield et al., 2001, Dudal et al., 2004, Lue et al., 1996). Specifically, these hallmarks occur in the brain regions of the cerebral cortex and hippocampus, which is classically related to declining cognitive function (Manczak et al., 2018). Moreover, it has previously been found that the aggregation of Aβ in the prefrontal cortex (PFC) and amygdala, the essential emotion regulating regions, is positively associated with the anxiety-like behavior in AD transgenic mice and AD patients (Davis and Whalen, 2001, España et al., 2010, Ramakers et al., 2012). Besides, the dysfunction of the hypothalamic-pituitaryadrenal (HPA) axis in patients with AD has been reported in several studies (Buckley et al., 2008, Pietrzak et al., 2017). Thus, it is speculated that the above changes may affect neural activity disorders such as cognitive and emotional dysfunction due to they gradually emerged in different brain regions.
Although the pathogenesis of AD remains unclear, a growing body of evidence suggests that the microbiota-gut-brain axis plays a pivotal role in adjusting brain functions (Sampson and Mazmanian, 2015, Wang et al., 2019b). It has been found that the gut microbiome of AD patients is significantly altered compared with healthy individuals (Vogt et al., 2017). It has been reported that the administration of probiotics such as microbes of Lactobacilli prevented cognitive decline and anxiety in both humans and animal studies (Messaoudi et al., 2011, Savignac et al., 2014). The altered gut microbiota also appears to be associated with Aβ accumulation (Luca et al., 2019, Minter et al., 2016). Interestingly, it has also been demonstrated that Lactobacillus and Bifidobacterium can improve the HPA axis function and modulate the behavior stress response (Ait-Belgnaoui et al., 2018, Frankiensztajn et al., 2020). Therefore, microbiota composition changes were closely relevant to behavioral disorders and psychiatric disturbance. Targeting modulation of gut homeostasis may be feasible for cognitive impairment and mood dysfunction of AD.
Mannan oligosaccharide (MOS) is one of the prebiotics derived from Konjac and the outer cell-wall membrane of bacteria, plants, or yeast (Pangsri et al., 2015). Various studies have indicated that MOS treatment can markedly reduce inflammation, prevent obesity, and strengthen the immune system via its mediating effects on gut microbiota (Ferenczi et al., 2016, Hoving et al., 2018b, Wang et al., 2018). Our recent study showed that reshaped gut microbiota alleviated the cognitive deficits and anxious behaviors in a mouse model by generating beneficial microbial metabolites such as short-chain fatty acids (SCFAs) (Liu et al., 2020). Dietary supplementation of MOS could suppress the appetite and systemic insulin resistance of obese mice by reshaping the gut microbial composition and enhancing the formation of SCFAs (Yan et al., 2019). SCFAs are the end-products of prebiotic fermentation, speculated to act as bridges of the microbiota-gut-brain axis (Slavin, 2013). It has been reported that SCFAs treatment prevents neuronal injury by inhibiting neuroinflammation and exhibits behavior-specific antidepressant and anti-anxiety effects in animal models (Matt et al., 2018, van de Wouw et al., 2018). Here, we hypothesized that MOS supplementation could ameliorate behavioral deficits containing memory loss and anxiety during AD development by enhancing SCFAs formation.
The present research explored the beneficial effects of MOS on cognitive and behavioral disorders in 5xFAD-Tg mice, a classic transgenic AD mouse model (Oakley et al., 2006). The memory deficit and non-cognitive behavioral tests were conducted on the impact of MOS on cognitive impairment and emotionality disorders in AD mice. To detect the physiological indicators of the brain, the Aβ accumulation, neuroinflammatory response, oxidative damage, and HPA axis activity were investigated. Moreover, the gut microbiota and metabolites SCFAs were characterized. The correlation analysis between the butyrate levels and other biochemical indexes was conducted, and a SCFAs supplementation experiment was established to confirm the mediating roles of these microbial metabolites involved in the neuroprotective effects of the MOS treatment.
Section snippets
Animals
The male 5xFAD-transgenic mice (Stock No: 006554) on a congenic C57BL6 background were provided by the Jackson Laboratory (Bar Harbor, ME, USA). The 5xFAD mice carry human amyloid precursor protein (APP) as well as the human presenilin 1 (PSEN1) transgenes with a total of five AD-related mutations, including the Swedish (K670N/M671L), Florida (I716V), and London (V717I) mutations in APP, and the M146L and L286V mutations in PSEN1. The 5xFAD mice periodically backcrossed generations with female
Effects of MOS treatment on cognitive impairments in 5xFAD mice
The animal genotype identification and experimental workflow were conducted as described in the Methods & materials section and as shown in Fig. S1A and 1A. During the experiment, there was no significant effect of genotype and MOS, as well as no interaction effect on body weight gain, food intake, and water intake, suggesting that the MOS treatment had no effects on the energy intake and body weight changes in the AD mice (Fig. 1B-E).
To investigate the protective effects of MOS on the
Discussion
The current study found that MOS supplementation significantly attenuates the cognitive deficits and anxiety-like behaviors in the male transgenic AD mice model. MOS treatment significantly reduced the Aβ accumulation and suppressed the expressions of APP and Bace1 in the brain of AD mice. Importantly, MOS treatment significantly inhibited the neuroinflammation and oxidative stress in the CNS of the AD mice, which partly explained the neuroprotective effects of MOS. MOS also balanced the HPA
Author contribution
QL and ZL designed the experiments; QL, YX, QW, JL, PL, XM, KL, and ZL performed and analyzed the experiments; QL, QW, and ZL interpreted the data; QL and WC prepared figures; QL and ZL wrote the manuscript; XL and ZL supervised the work. All authors approved the final version of the manuscript.
Acknowledgments
This work was financially supported by the National Natural Science Foundation of China (Nos. 81871118 and 81803231), a General Financial Grant from China Postdoctoral Science Foundation (No. 2016M602867), a Special Financial Grant from China Postdoctoral Science Foundation (No. 2018T111104), and the Innovative Talent Promotion Program-Technology Innovation Team (2019TD-006). Dr. Zhigang Liu is also funded by the Tang Cornell-China Scholars Program from Cornell University in the U.S. and the
References (85)
- et al.
Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid β-peptide
Trends Mol. Med.
(2001) - et al.
Marble-burying behavior test as a murine model of compulsive-like behavior
J. Pharmacol. Toxicol. Methods.
(2020) - et al.
Inflammation occurs early during the Aβ deposition process in TgCRND8 mice
Neurobiol. Aging.
(2004) - et al.
Intraneuronal β-Amyloid Accumulation in the Amygdala Enhances Fear and Anxiety in Alzheimer's Disease Transgenic Mice
Biol. Psychiatry.
(2010) - et al.
The microbiota and the hypothalamus-pituitary-adrenocortical (HPA) axis, implications for anxiety and stress disorders
Curr. Opin. Neurobiol.
(2020) - et al.
Short-chain fatty acid receptor GPR41-mediated activation of sympathetic neurons involves synapsin 2b phosphorylation
FEBS Letters.
(2012) - et al.
Neuropsychiatric symptoms as early manifestations of emergent dementia: Provisional diagnostic criteria for mild behavioral impairment
Alzheimers. Dement.
(2016) - et al.
Sensitivity to the depressogenic effect of stress and HPA-axis reactivity in adolescence: A review of gender differences
Neurosci. Biobehav. Rev.
(2011) - et al.
The HPA axis in major depression: classical theories and new developments
Trends Neurosci.
(2008) - et al.
Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat
J. Neurosci. Methods.
(1985)
Plasma Cortisol, Brain Amyloid-β, and Cognitive Decline in Preclinical Alzheimer's Disease: A 6-Year Prospective Cohort Study
Biol. Psychiatry.
Anxiety, defence and the elevated plus-maze
Neurosci. Biobehav. Rev.
Control of Brain Development, Function, and Behavior by the Microbiome
Cell Host Microbe.
Inflammation in Alzheimer's disease: Lessons learned from microglia-depletion models
Brain Behav. Immun.
The molecular basis of the prevention of Alzheimer's disease through healthy nutrition
Exp. Gerontol.
Short-chain fatty acids administration is protective in colitis-associated colorectal cancer development
J. Nutr. Biochem.
Stimulation of butyrate production by gluconic acid in batch culture of pig cecal digesta and identification of butyrate-producing bacteria
J. Nutr.
The genetic landscape of Alzheimer disease: clinical implications and perspectives
Genet. Med.
Helicobacter pylori filtrate impairs spatial learning and memory in rats and increases β-amyloid by enhancing expression of presenilin-2
Front. Aging Neurosci.
Molecular and crystal structure of konjac glucomannan in the mannan II polymorphic form
Carbohydr. Res.
Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease
Curr. Pharm. Design.
Bifidobacterium longum and Lactobacillus helveticus Synergistically Suppress Stress-related Visceral Hypersensitivity Through Hypothalamic-Pituitary-Adrenal Axis Modulation
J Neurogastroenterol Motil.
Glucocorticoid-Related Molecular Signaling Pathways Regulating Hippocampal Neurogenesis
Neuropsychopharmacology.
Effects of Mannooligosaccharides from Coffee on Microbiota and Short Chain Fatty Acids in Rat Cecum
Food Sci. Technol. Res.
Alzheimer's disease
BMJ (Clinical research ed).
Is AD a Stress-Related Disorder? Focus on the HPA Axis and Its Promising Therapeutic Targets
Front Aging Neurosci.
LPS-induced Murine Neuroinflammation Model: Main Features and Suitability for Pre-clinical Assessment of Nutraceuticals
Curr. Neuropharmacol.
The role of short-chain fatty acids in microbiota-gut-brain communication
Nat. Rev. Gastroenterol. Hepatol.
The amygdala: vigilance and emotion
Mol. Psychiatr.
The Pro-inflammatory Effects of Glucocorticoids in the Brain
Front. Endocrinol.
Oligomannan Prebiotic Attenuates Immunological, Clinical and Behavioral Symptoms in Mouse Model of Inflammatory Bowel Disease
Sci. Rep.
Sodium Butyrate Reduces Brain Amyloid-β Levels and Improves Cognitive Memory Performance in an Alzheimer's Disease Transgenic Mouse Model at an Early Disease Stage
J. Alzheimers Dis.
Anxiety and Alzheimer's disease
J. Geriatr. Psychiatry Neurol.
Targeting psychologic stress signaling pathways in Alzheimer's disease
Mol. Neurodegener.
Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer's disease-type beta-amyloid neuropathological mechanisms
Expert Rev. Neurother.
Dietary fiber and prebiotics and the gastrointestinal microbiota
Gut microbes.
Dietary Mannan Oligosaccharides Modulate Gut Microbiota, Increase Fecal Bile Acid Excretion, and Decrease Plasma Cholesterol and Atherosclerosis Development
Mol. Nutr. Food Res.
Dietary yeast-derived mannan oligosaccharides have immune-modulatory properties but do not improve high fat diet-induced obesity and glucose intolerance
PLoS One.
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These authors contribute equally.