Suppression of gut dysbiosis by Bifidobacterium longum alleviates cognitive decline in 5XFAD transgenic and aged mice

Background: Iron homeostasis disorder and neuroinflammation are the most commonly known factors that promote the occurrence and development of cognitive impairment in people. Dexmedetomidine has an anti-inflammatory effect, and it reduces the incidence of postoperative cognitive dysfunction. Therefore, the aim of this study is to verify whether dexmedetomidine could improve lipopolysaccharide-induced iron homeostasis disorder in aged mice, and show neuroprotective effect. Methods: First part, forty 12 month old male Kunming(KM) mice were divided into group N and group D: Normal saline group (group N), Dexmedetomidine group (group D). Second part, sixty 12-month-old male KM mice were divided into the following three groups: Normal saline group (group N), Lipopolysaccharide group (group LPS) and Dexmedetomidine + Lipopolysaccharide group (group D + LPS). The mice in group D + LPS were given dexmedetomidine, and given LPS intraperitoneally 2 h later. Mice underwent an oriented navigation test and a space exploration test in the Morris Water maze (MWM) test. The expression levels of Interleukin-6 ( IL-6), L-ferritin (FTL) and Transferrin receptor-1 (TfR1) in hippocampus were detected by the Western blot analysis; the hippocampal hepcidin mRNA was detected by Real-time PCR(RT-PCR); the reactive oxygen species (ROS) in the hippocampus was measured using ROS test kit. Results: Dexmedetomidine improved the cognitive decline induced by LPS. Dexmedetomidine reduced the level of hippocampal IL-6, and it attenuated the increase in their levels caused by LPS. It had no effect on hippocampal hepcidin mRNA, FTL, TfR1 and ROS but it could attenuate the increase caused by LPS. Conclusion: Dexmedetomidine has no effect on iron metabolism pathway, but it can improve the cognitive decline and the iron disorder by reducing neuroinflammation and oxidative stress. The research indicates that dexmedetomidine plays a neuroprotective role.

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Engram reactivation during memory retrieval predicts long-term memory performance in aged mice

10.1101/2020.01.12.903088 ◽

2020 ◽

Author(s):

Kubra Gulmez Karaca ◽

David V.C. Brito ◽

Benjamin Zeuch ◽

Ana M.M. Oliveira

Keyword(s):

Cognitive Decline ◽

Memory Performance ◽

Underlying Mechanism ◽

Long Term Memory ◽

Memory Recall ◽

Term Memory ◽

Aged Mice ◽

Neuronal Ensembles ◽

Age Related

AbstractAge-related cognitive decline preferentially targets long-lasting episodic memories that require intact hippocampal function. Memory traces (or engrams) are believed to be encoded within the neurons activated during learning (neuronal ensembles), and recalled by reactivation of the same population. However, whether engram reactivation dictates memory performance in late life is not known. Here, we labelled neuronal ensembles formed during object location recognition learning in the dentate gyrus, and analyzed the reactivation of this population by long-term memory recall in young adult, cognitively impaired- and unimpaired-aged mice. We found that reactivation of memory-encoding neuronal ensembles at long-term memory recall was disrupted in impaired- but not unimpaired-aged mice. Furthermore, we showed that the memory performance in the aged population correlated with the degree of engram reactivation at long-term memory recall. Overall, our data implicates recall-induced engram reactivation as a prediction factor of memory performance throughout aging. Moreover, our findings suggest impairments in neuronal ensemble stabilization and/or reactivation as an underlying mechanism in age-dependent cognitive decline.

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Lactobacillus rhamnosus and Bifidobacterium longum alleviate colitis and cognitive impairment in mice by regulating IFN-γ to IL-10 and TNF-α to IL-10 expression ratios

Scientific Reports ◽

10.1038/s41598-021-00096-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xiaoyang Ma ◽

Yoon-Jung Shin ◽

Hyo-Min Jang ◽

Min-Kyung Joo ◽

Jong-Wook Yoo ◽

...

Keyword(s):

Cognitive Impairment ◽

Intraperitoneal Injection ◽

Bifidobacterium Longum ◽

Lactobacillus Rhamnosus ◽

Natural Killer Cell Cytotoxicity ◽

Gut Dysbiosis ◽

Tnf Α ◽

Ifn Γ ◽

Immune Imbalance

AbstractGut lactobacilli and bifidobacteria on the immune homeostasis. Therefore, to understand the mechanism in vivo, we selected human fecal Lactobacillus rhamnosus NK210 and Bifidobacterium longum NK219, which strongly suppressed the IFN-γ to IL-10 expression (IIE) ratio in lipopolysaccharide-stimulated macrophages. Thereafter, we examined their effects on the endotoxin, antibiotics, or antitumor drug-stimulated immune imbalance in mice. Intraperitoneal injection of lipopolysaccharide and oral gavage of ampicillin increased IFN-γ and TNF-α expression in the spleen, colon, and hippocampus, while IL-10 expression decreased. However, intraperitoneal injection of cyclophosphamide suppressed IFN-γ, TNF-α, and IL-10 expression. LPS exposure induced splenic natural killer cell cytotoxicity against YAC-1 cells (sNK-C) and peritoneal macrophage phagocytosis against Candida albicans (pMA-P) activities, while cyclophosphamide and ampicillin treatments suppressed sNK-C and pMA-P activities. However, LPS, ampicillin, cyclophosphamide all increased IIE and TNF-α to IL-10 expression (TIE) ratios. Oral administration of NK210 and/or NK219 significantly reduced LPS-induced sNK-C, pMA-P, and IFN-γ expression, while cyclophosphamide- or ampicillin-suppressed sNK-C and pMA-P activities, cyclophosphamide-suppressed IFN-γ, TNF-α, and IL-10 expression, and ampicillin-suppressed IL-10 expression increased. Nevertheless, they suppressed LPS-, ampicillin-, or cyclophosphamide-induced IIE and TIE ratios, cognitive impairment, and gut dysbiosis. In particular, NK219, but not NK210, increased the IIE expression ratio in vitro and in vivo, and enhanced sNK-C and pMA-P activities in normal control mice, while cognitive function and gut microbiota composition were not significantly affected. These findings suggest that NK210, Lactobacillus sp, and NK219, Bifidobacterium additively or synergistically alleviate gut dysbiosis, inflammation, and cognitive impairment with immune imbalance by controlling IIE and TIE ratios.

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Reversing Cognitive Decline in Aging: Reversible Mechanistic Defects and a Novel Nutritional Intervention

Innovation in Aging ◽

10.1093/geroni/igaa057.3156 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 857-857

Author(s):

Rajagopal Sekhar ◽

George Taffet

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Older Adults ◽

Cognitive Decline ◽

Mitochondrial Dysfunction ◽

Nutritional Intervention ◽

Open Label ◽

Aged Mice ◽

Naturally Occurring ◽

Glutathione Deficiency

Abstract Aging is the biggest risk factor for cognitive-decline and Alzheimer’s disease (AD), but underlying mechanisms are not well-understood and interventions are lacking. Cognitive-decline in AD has been associated with deficiency of glutathione, (the most abundant, intracellular, antioxidant protein), elevated oxidative-stress, insulin-resistance and increased inflammation. We identified and reported that glutathione-deficiency and oxidative-stress in older-adults occur due to decreased availability of precursor amino-acids glycine and cysteine, and can be corrected with GlyNAC (a combination of glycine and the cysteine precursor N-acetylcysteine). We hypothesized that cognitive decline in older-adults is linked to glutathione-deficiency, mitochondrial-dysfunction, oxidative-stress, insulin-resistance, and inflammation. The first abstract discusses the rationale and findings of an open-label clinical trial: compared to young-humans, older-adults had cognitive-decline, glutathione-deficiency, mitochondrial-dysfunction, abnormal glucose-metabolism and insulin-resistance, oxidative-stress, endothelial-dysfunction and inflammation. These defects were improved/reversed by supplementing GlyNAC for 24-weeks, but benefits receded on stopping GlyNAC for 12-weeks. The second abstract presents a study in 8 young (20-weeks old) and 16 aged (90-weeks old) wild-type male C57BL/6J mice where we found that aged-mice had naturally-occurring cognitive-impairment, and brain defects in glutathione-deficiency, oxidative-stress, glucose-transport, mitochondrial glucose-oxidation, insulin-resistance, endoplasmic-reticulum stress, autophagy, mitophagy, inflammation, senescence, genomic and telomere damage. Aged-mice received either GlyNAC or isonitrogenous-placebo supplementation for 8-weeks, and only GlyNAC-fed mice improved cognition and brain defects. Collectively these data highlights the discovery of novel and reversible mechanistic defects in older-adults and aged-mice with naturally-occurring cognitive-decline, and identifies that supplementing GlyNAC can improve brain-health and cognition. These findings could have important implications for reversing cognitive-decline in older-adults, and AD.

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Abstract TP91: Stroke Induced Respiratory Dysfunction: Age, Apnea and Cognitive Decline

Stroke ◽

10.1161/str.48.suppl_1.tp91 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Anthony Patrizz ◽

Hilda Ahnstedt ◽

Louise McCullough

Keyword(s):

Cognitive Decline ◽

Minute Ventilation ◽

Cognitive Outcomes ◽

Whole Body ◽

Escape Time ◽

Cognitive Tests ◽

Respiratory Dysfunction ◽

Young Stroke ◽

Aged Mice ◽

Post Stroke

Respiratory dysfunction is a common complication of stroke, with an incidence more than 60%, leading to prolonged recovery and increased mortality. Despite the high prevalence of stroke induced respiratory dysfunction (SIRD) little is known regarding how SIRD influences recovery and cognitive outcomes after ischemic stroke. Studies in non-stroke populations have shown that individuals with respiratory dysfunction are drastically more likely to develop cognitive impairment. We propose stroke will induce chronic respiratory dysfunction, instability, and apnea in mice, which are linked to higher mortality and greater post-stroke cognitive deficits. Respiratory dysfunction will be related to progressive cognitive decline following middle cerebral artery occlusion (MCAo) that is worse in aged mice. Whole body plethysmography was performed on C57/B6 young (2-3 month)/aged (20 month) male mice to establish baseline frequency (BPM), tidal volume, minute ventilation and apnea frequency. Animals were exposed to a variety of gas conditions to assess the contribution of peripheral and central chemoreceptors. Mice were subjected to 60 MCAO, producing chronic respiratory dysfunction, instability and apnea, or sham surgery. Days 3, 7 and weekly thereafter plethysmography and a variety of cognitive tests were performed to track respiratory dysfunction and progressive cognitive decline. Young and aged mice displayed hypoventilation (young stroke 181.4±22 vs. sham 264±35 bpm p<.05 and aged stroke 233.7±46.6 bpm vs. sham 369.4±25.9 p<.05) and increased apneas (young stroke 6.8±1.2 vs. 0.8±.8 apnea/min p<.01; aged stroke 16±1 vs. 12±1.5 apneas/min) at day 3 post-stroke. Six weeks later mice were stratified based on # apneas/min into minor (<5 apneas/min N=8) and moderate/severe (>5 apneas/min N=3). Mice with minor apneas perform better in a variety of cognitive tests. Fear conditioning (freezing behavior minor 1.47±.24s/event vs. mod .74±.07s/event, p=.02), Barnes maze: Escape time minor 158.5±35.2 sec vs. 217.9±82. NORT: ratio time novel/familiar object minor 2.2±.6 vs. 1.1±.3. Suggesting incidence of apneas as an indicator of cognitive decline. Therefore, the treatment of respiratory instability is a viable prospect to improve cognitive outcomes.

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Gut dysbiosis develops before metabolic disturbance and cognitive decline in high-fat diet–induced obese condition

Nutrition ◽

10.1016/j.nut.2019.110576 ◽

2020 ◽

Vol 69 ◽

pp. 110576 ◽

Cited By ~ 8

Author(s):

Napatsorn Saiyasit ◽

Titikorn Chunchai ◽

Dillon Prus ◽

Kanokphong Suparan ◽

Pansa Pittayapong ◽

...

Keyword(s):

Cognitive Decline ◽

High Fat Diet ◽

Metabolic Disturbance ◽

High Fat ◽

Gut Dysbiosis

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Divergence in the metabolome between natural aging and Alzheimer’s disease

Scientific Reports ◽

10.1038/s41598-020-68739-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Holly C. Hunsberger ◽

Bennett P. Greenwood ◽

Vladimir Tolstikov ◽

Niven R. Narain ◽

Michael A. Kiebish ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Neurodegenerative Disorder ◽

Memory Deficits ◽

The United States ◽

Contextual Fear Conditioning ◽

System Level ◽

Aged Mice ◽

Age Related

Abstract Alzheimer’s disease (AD) is a progressive and debilitating neurodegenerative disorder and one of the leading causes of death in the United States. Although amyloid plaques and fibrillary tangles are hallmarks of AD, research suggests that pathology associated with AD often begins 20 or more years before symptoms appear. Therefore, it is essential to identify early-stage biomarkers in those at risk for AD and age-related cognitive decline (ARCD) in order to develop preventative treatments. Here, we used an untargeted metabolomics analysis to define system-level alterations following cognitive decline in aged and APP/PS1 (AD) mice. At 6, 12, and 24 months of age, both control (Ctrl) and AD mice were tested in a 3-shock contextual fear conditioning (CFC) paradigm to assess memory decline. AD mice exhibited memory deficits across age and these memory deficits were also seen in naturally aged mice. Prefrontal cortex (PFC), hippocampus (HPC), and spleen were then collected and analyzed for metabolomic alterations. A number of significant pathways were altered between Ctrl and AD mice and naturally aged mice. By identifying systems-level alterations following ARCD and AD, these data could provide insights into disease mechanisms and advance the development of biomarker panels.

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Reversing Mitochondrial, Metabolic and Molecular Defects in the Brain Improves Cognition in Aged Mice

Innovation in Aging ◽

10.1093/geroni/igaa057.3158 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 857-858

Author(s):

Rajagopal Sekhar ◽

Premranjan Kumar

Keyword(s):

Oxidative Stress ◽

Cognitive Decline ◽

Whole Body ◽

Cognitively Impaired ◽

The Novel ◽

Open Label ◽

Molecular Defects ◽

Aged Mice ◽

Systemic Insulin Resistance ◽

The Brain

Abstract Age-associated cognitive-decline is a risk factor for Alzheimer’s disease (AD), but mechanisms are not well understood, and interventions are lacking. Rodent studies on AD have not led to therapeutic breakthroughs for cognitively-impaired humans. In an open-label trial in older-adults we found that supplementing GlyNAC (glutathione precursors glycine and N-acetylcysteine) improved cognitive-decline, defects in whole-body mitochondrial-function, and systemic insulin-resistance, oxidative-stress, and inflammation. We hypothesized that aged-mice will have similar defects in the brain, and studied male C57BL/6J mice as follows: young-mice (20w) were compared to two-groups of aged-mice (90-weeks) receiving either GlyNAC or isonitrogenous-placebo diets for 8-weeks. GlyNAC-supplementation improved cognition, and the following measures in the brain: glutathione-concentrations, glucose-transporters in blood-brain-barrier and neurons, mitochondrial glucose-oxidation, oxidative-stress, endoplasmic-reticulum stress, autophagy, mitophagy, inflammation, senescence, genomic and telomere damage. These data provide mechanistic insights into the novel and beneficial role of GlyNAC supplementation to reverse cognitive-decline in aging, and holds promise for human AD.

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