Iso-α-acids, Hop-Derived Bitter Components of Beer, Attenuate Age-Related Inflammation and Cognitive Decline

With the aging population rapidly increasing worldwide, preventive measures and treatments for age-related cognitive decline and dementia are of utmost importance. We have previously demonstrated that the consumption of iso-α-acids (IAA), which are hop-derived bitter compounds in beer, prevents the formation of disease pathology in a transgenic mouse model of Alzheimer’s disease (AD). However, the effect of IAA consumption on age-related cognitive decline is unknown. In the present study, we examined the effect of long-term and short-term dietary consumption of IAA, on age-related memory impairments and inflammation in the hippocampus of aged mice. When compared with young mice, aged mice showed impairment in spatial working memory during the Y-maze spontaneous alternation test, impairment in object recognition memory during the novel object recognition test (NORT), a pro-inflammatory hippocampal microglial phenotype with increased CD86 expression and inflammatory cytokine production, increased levels of glutamate and amyloid β1–42, and decreased levels of dopamine (DA). In aged mice fed IAA for 3 months, the age-related alterations in memory, microglial inflammation, and glutamate, amyloid β1–42, and DA levels were all significantly attenuated. Additionally, the oral administration of IAA for 7 days in aged mice with memory impairment, also improved spatial and object recognition memory. These results suggest that IAA consumption prevents inflammation in the hippocampus and ameliorates age-related cognitive decline

Hop-Derived Iso-α-Acids in Beer Improve Visual Discrimination and Reversal Learning in Mice as Assessed by a Touch Panel Operant System

Dementia and cognitive decline have become worldwide health problems due to rapid growth of the aged population in many countries. We previously demonstrated that single or short-term administration of iso-α-acids, hop-derived bitter acids in beer, improves the spatial memory of scopolamine-induced amnesia model mice in the Y-maze and enhances novel object recognition in normal mice via activation of the vagus nerve and hippocampal dopaminergic system. However, these behavioral tests do not replicate the stimulus conditions or response requirements of human memory tests, and so may have poor translational validity. In this report, we investigated the effects of iso-α-acids on visual discrimination (VD) and reversal discrimination (RD) using a touch panel-based operant system similar to that used for human working memory tests. In the VD task, scopolamine treatment reduced correct response rate and prolonged response latency in mice, deficits reversed by prior oral administration of iso-α-acids. In the RD task, administration of iso-α-acids significantly increased correct response rate compared to vehicle administration. Previous studies have reported that dopamine signaling is involved in both VD and RD learning, suggesting that enhancement of dopamine release contributes to improved memory performance in mice treated with iso-α-acids. Taken together, iso-α-acids improve VD and RD learning, which are considered high-order cognitive functions. Given the translational advantages of the touch panel-based operant system, the present study suggests that iso-α-acids could be effective for improvement of working memory in human dementia patients

Iso-α-Acids, Bitter Components in Beer, Suppress Inflammatory Responses and Attenuate Neural Hyperactivation in the Hippocampus

Due to the growth in aging populations worldwide, prevention and therapy for age-related cognitive decline and dementia are in great demand. We previously demonstrated that long-term intake of iso-α-acids, which are hop-derived bitter compounds found in beer, prevent Alzheimer’s pathology in a rodent model. On the other hand, the effects of iso-α-acids on neural activity in Alzheimer’s disease model mice have not been investigated. Here, we demonstrated that short-term intake of iso-α-acids suppresses inflammation in the hippocampus and improves memory impairment even after disease onset. Importantly, we demonstrated that short-term administration of iso-α-acids attenuated the neural hyperactivation in hippocampus. In 6-month-old 5 × FAD mice exhibiting hippocampus inflammation and memory impairment, oral administration of iso-α-acids for 7 days reduced inflammatory cytokines, including MIP-1α and soluble Aβ and improved object memory in the novel object recognition test. In 12-month-old J20 mice, intake of iso-α-acids for 7 days also suppressed inflammatory cytokines and soluble Aβ in the brain. Manganese-enhanced magnetic resonance imaging (MEMRI) of hippocampi of J20 mice showed increased manganese compared with wild type mice, but iso-α-acids canceled this increased MEMRI signal in J20 mice, particularly in the hippocampus CA1 and CA3 region. Taken together, these findings suggest that short-term intake of iso-α-acids can suppress hippocampus inflammation even after disease onset and improve hyper neural activity in Alzheimer’s disease model mice

Matured Hop Bitter Acids in Beer Improve Lipopolysaccharide-Induced Depression-Like Behavior

Recent studies have demonstrated a close association between neural inflammation and development of mental illnesses, such as depression. Clinical trials have reported that treatment with non-steroidal anti-inflammatory drugs is associated with reduced risk of depression. Moreover, nutritional approaches for the prevention and management of depression have garnered significant attention in recent years. We have previously demonstrated that iso-α-acids (IAAs)—the bitter components in beer—suppress hippocampal microglial inflammation, thereby improving cognitive decline. However, effects of hop-derived components other than IAAs on inflammation have not been elucidated. In the present study, we demonstrated that consumption of matured hop bitter acids (MHBAs) generated from α- and β-acids, which show a high similarity with the chemical structure of IAAs, suppress lipopolysaccharide (LPS)-induced cytokine productions in the brain. MHBAs administration increased norepinephrine (NE) secretion and reduced immobility time which represents depression-like behavior in the tail suspension test. Moreover, MHBAs components, including hydroxyallohumulinones and hydroxyalloisohumulones, reduced LPS-induced immobility time. Although further researches are needed to clarify the underlying mechanisms, these findings suggest that MHBAs reduce inflammatory cytokine productions and increase NE secretion, thereby improving depression-like behavior. Similarly, inoculation with LPS induced loss of dendritic spines, which was improved upon MHBAs administration. Additionally, vagotomized mice showed attenuated improvement of immobility time, increase in NE level, and improvement of dendrite spine density following MHBAs administration. Therefore, MHBAs activate the vagus nerve and suppress neuronal damage and depression-like behavior induced by inflammation

Identifcation of P2Y receptors involved in oleamide-suppressing infammatory responses in murine microglia and human dendritic cells

Abstract Microglia, a type of immune cell in the central nervous system, are involved in inflammation leading to neurodegenerative diseases. We previously identified oleamide from fermented dairy products as a neuroprotective compound suppressing microglial inflammation. Oleamide is an endocannabinoid and displays anti-inflammatory activity via the cannabinoid-2 (CB2) receptor; however, the mechanism underlying this anti-inflammatory activity has not been fully elucidated. Here, we found that the suppressive effect of oleamide on microglial tumor necrosis factor-α (TNF-α) production was canceled by inhibitors of G-protein-coupled receptor (GPCR) downstream signaling but not by a CB2 antagonist, suggesting that GPCRs other than CB2 are involved in the anti-inflammatory effects of oleamide. An extensive screen for GPCRs using a transforming growth factor-α shedding assay system identified P2Y1, P2Y4, P2Y6, P2Y10, and P2Y11 as candidates for the oleamide target. P2Y1 and P2Y10 agonists suppressed microglial TNF-α production, while a pan P2 receptor antagonist canceled the suppressive effect. Furthermore, we observed a relationship between the P2Y1 agonistic activities and the suppressive activities of oleamide and its analogs. Taken together, our results suggest that, in addition to CB2, P2Y type receptors are the potential targets of oleamide, and P2Y1 plays a role in the suppression of microglial inflammatory responses by oleamide. (200/200 words

Blocking of FcR Suppresses the Intestinal Invasion of Scrapie Agents

Prion diseases are a family of neurodegenerative zoonotic foodborne disorders. Although prions can be transmitted orally, the mechanism by which prions are incorporated into the intestine remains unclear. Our previous studies have shown that an abnormal isoform of prion protein (PrPSc), which is the main component of prions, was efficiently incorporated into the intestine in suckling mice but not in weaned mice. Furthermore, suckling SCID mice lacking maternal antibodies showed decreased uptake of PrPSc into the intestine compared with suckling wild-type mice, while the lack of PrPSc uptake into the intestine of suckling SCID mice was rescued by the oral administration of IgG. These findings raise the possibility that the neonatal Fc receptor (nFcR), which contributes to the uptake of maternal antibodies into the intestine, plays a role in PrPSc incorporation into the intestine. The present immunohistochemical study further showed that the FcR blocker Z-ε-aminocaproic acid (ZAA) inhibited PrPSc incorporation into the intestinal villi of suckling mice, supporting the above mentioned concept. Therefore, our findings provide strong evidence that nFcR and maternal antibodies are involved in PrPSc incorporation into the intestine before the weaning period

Supplementation With Whey Peptide Rich in β-Lactolin Improves Cognitive Performance in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Study

Epidemiological reports showed that consumptions of fermented dairy products are beneficial for cognitive decline in elderly. Our previous preclinical studies have demonstrated that intakes of whey peptide rich in the β-lactolin [β-lactopeptide of glycine-thereonine-tryptophan-tyrosine (GTWY)] improve memory and attention by regulating monoamine system, and clinical study using neuropsychological test suggested that consumptions with GTWY-rich whey peptide enhance cognitive performance associated with the frontal cortex activity. However, corresponding interventional studies in humans are limited. Objectives: to evaluate the effects of the whey peptide on cognitive functions in healthy older adults using a randomized, double-blinded, placebo-controlled trial design. 114 healthy subjects aged 50–75 were supplemented with the whey peptide or placebo for 12 weeks, and changes in cognitive function were assessed using neuropsychological tests at weeks 0, 6, and 12 of the intervention. Neuropsychological tests included assessments for memory functions (subtests from Wechsler memory scale-revised, standard verbal paired-associate learning test, and recognition memory test for faces), assessments for attention (cancelation and detection tests), and assessments for general cognitive functions (repeatable battery for assessments of neuropsychological status). Cerebral blood flow was also assessed using near-infrared spectroscopy (NIRS) after 6 weeks of intervention. This study was registered on the 19 November, 2017 in the database of the University Hospital Medical Information Network (UMIN) prior to enrollment of subjects (Registration No. UMIN000030461: https://www.umin.ac.jp/ctr/index-j.htm). In the whey peptide group, visual paired-associates I and visual cancelation tests were significantly improved compared with those in the placebo group at weeks 6 and 12 of the intervention, respectively. Visuospatial and constructional scores of the repeatable battery for assessments of neuropsychological status and standard verbal paired-associate learning tests (S-PA) also tended to be improved by the intervention at week 12. Daily intakes of GTWY-rich whey peptide show beneficial effects on cognitive performance, especially associative learning memory and control of attention, in healthy older adults and might prevent age-related cognitive declines

Spherical Lactic Acid Bacteria Activate Plasmacytoid Dendritic Cells Immunomodulatory Function via TLR9-Dependent Crosstalk with Myeloid Dendritic Cells

Plasmacytoid dendritic cells (pDC) are a specialized sensor of viral and bacterial nucleic acids and a major producer of IFN-α that promotes host defense by priming both innate and acquired immune responses. Although synthetic Toll-like receptor (TLR) ligands, pathogenic bacteria and viruses activate pDC, there is limited investigation of non-pathogenic microbiota that are in wide industrial dietary use, such as lactic acid bacteria (LAB). In this study, we screened for LAB strains, which induce pDC activation and IFN-α production using murine bone marrow (BM)-derived Flt-3L induced dendritic cell culture. Microbial strains with such activity on pDC were absent in a diversity of bacillary strains, but were observed in certain spherical species (Lactococcus, Leuconostoc, Streptococcus and Pediococcus), which was correlated with their capacity for uptake by pDC. Detailed study of Lactococcus lactis subsp. lactis JCM5805 and JCM20101 revealed that the major type I and type III interferons were induced (IFN-α, -β, and λ). IFN-α induction was TLR9 and MyD88-dependent; a slight impairment was also observed in TLR4-/- cells. While these responses occurred with purified pDC, IFN-α production was synergistic upon co-culture with myeloid dendritic cells (mDC), an interaction that required direct mDC-pDC contact. L. lactis strains also stimulated expression of immunoregulatory receptors on pDC (ICOS-L and PD-L1), and accordingly augmented pDC induction of CD4+CD25+FoxP3+ Treg compared to the Lactobacillus strain. Oral administration of L. lactis JCM5805 induced significant activation of pDC resident in the intestinal draining mesenteric lymph nodes, but not in a remote lymphoid site (spleen). Taken together, certain non-pathogenic spherical LAB in wide dietary use has potent and diverse immunomodulatory effects on pDC potentially relevant to anti-viral immunity and chronic inflammatory disease

Preventive Effects of Dairy Products on Dementia and the Underlying Mechanisms

Alongside the rapid population aging occurring worldwide, the prevention of age-related memory decline and dementia has become a high priority. Dairy products have many physiological effects owing to their contents of lactic acid bacteria and the fatty acids and peptides generated during their fermentation. In particular, several recent studies have elucidated the effects of fermented dairy products on cognitive function. Epidemiological and clinical evidence has indicated that fermented dairy products have preventive effects against dementia, including Alzheimer’s disease. Recent preclinical studies have identified individual molecules generated during fermentation that are responsible for those preventive effects. Oleamide and dehydroergosterol have been identified as the agents responsible for reducing microglial inflammatory responses and neurotoxicity. In this review, the protective effects of fermented dairy products and their components on cognitive function, the mechanisms underlying those effects, and the prospects for their future clinical development will be discussed