Tryptophan-tyrosine dipeptide improves tau-related symptoms in tauopathy mice.

Neurodegenerative diseases involving pathological tau protein aggregation are collectively known as tauopathies and include Alzheimer's disease and Pick's disease. Recent studies show that the intake of tryptophan-tyrosine (Trp-Tyr)-related ß-lactopeptides, including ß-lactolin, attenuates cognitive decline in the elderly and prevents the amyloid pathology in mouse models of Alzheimer's disease. However, the effects of Trp-Tyr-related ß-lactopeptides on tau-related pathology have not been investigated. In the present study, we examined the effects of Trp-Tyr dipeptide intake on tauopathy in PS19 transgenic mice, a well-established tauopathy model. Intake of Trp-Tyr dipeptide improved the behavioral deficits observed in the open field test, prevented tau phosphorylation, and increased the dopamine turnover and synaptophysin expression in the frontal cortex. Levels of short-chain fatty acids in the cecum were lower in PS19 mice than those in wild-type mice and were increased by treatment with Trp-Tyr dipeptide. In addition, intake of Trp-Tyr dipeptide extended the lifespan of PS19 mice. These findings suggest that the intake of Trp-Tyr-related peptides improves tauopathy symptoms, resulting in improvements in behavioral deficits and longevity. Hence, the intake of Trp-Tyr-related peptides, including ß-lactolin, may be beneficial for preventing dementia.

[Hop Bitter Acids Activate the Brain-Gut Axis: Vagal Stimulus via Food Ingredients].

Maintenance and improvement of cognitive function and mood is important in an aging society. Preventive approaches, including diets used in daily life have received increasing attention in recent times. Clinical trials and preclinical studies have shown that hop bitter acids, which represent the bitter ingredients in beer, activate the bitter taste receptors and the brain-gut axis, which was shown to improve cognitive function and mood. Vagal stimulus via food ingredients may be a novel approach to maintain brain functions.

ß-Lactolin improves mitochondrial function in Aß-treated mouse hippocampal neuronal cell line and a human iPSC-derived neuronal cell model of Alzheimer's disease.

Mitochondrial dysfunctions are a key hallmark of Alzheimer's disease (AD). ß-Lactolin, a whey-derived glycine-threonine-tryptophan-tyrosine tetrapeptide, has been previously reported to prevent AD-like pathologies in an AD mouse model via regulation of microglial functions. However, the direct effect of ß-lactolin on neuronal cells and neuronal mitochondrial functions remains unknown. Here, we investigated the effects of ß-lactolin on mitochondrial functions in amyloid ß (Aß)-treated mouse hippocampal neuronal HT22 cells and human induced-pluripotent cell (hiPSC)-derived AD model neurons. Adding ß-lactolin to Aß-treated HT22 cells increased both the oxygen consumption rate and cellular ATP concentrations, suggesting that ß-lactolin improves mitochondrial respiration and energy production. Using high content image analysis, we found that ß-lactolin improved mitochondrial fragmentation, membrane potential, and oxidative stress in Aß-treated cells, eventually preventing neuronal cell death. From a mechanistic perspective, we found that ß-lactolin increased gene expression of mitofusin-2, which contributes to mitochondrial fusion events. Finally, we showed that ß-lactolin improves both mitochondrial morphologies and membrane potentials in hiPSC-derived AD model neurons. Taken together, ß-lactolin improved mitochondrial functions AD-related neuronal cell models and prevented neuronal cell death. The dual function of ß-lactolin on both neuron and microglia marks an advantage in maintaining neuronal health.

Effect of non-alcoholic beer containing matured hop bitter acids on mood states in healthy adults: A single-arm pilot study.

This study aimed to investigate the effect of non-alcoholic beer containing matured hop bitter acids on mood states among healthy adults older than 20 years. This study was an open-label longitudinal intervention design in which each participant served as their control. For 3 weeks, we evaluated the effect of non-alcoholic beer containing 35 mg of matured hop bitter acids on mood, sleep quality, and work performance. The data of 97 participants (age range: 23-72 years, median age: 42) were analyzed. After the intervention, we found that matured hop bitter acids significantly improved total mood state, including anxiety, depression, fatigue, and vigor, compared with the baseline. Furthermore, sleep quality and absolute presenteeism were significantly improved after the intervention compared with the baseline. The present exploratory study suggested that 3-week supplementation with matured hop bitter acids improved mood and peripheral symptoms in persons of a wide range of ages. Although further investigation is needed, the findings suggested that non-alcoholic beer in daily life might become a choice for maintaining mood states.

ß-Lactolin Reduces Age-Related Inflammation and Cognitive Decline.

With the rapid increase in aging populations worldwide, there has been an increase in demand for preventive and therapeutic measures for age-related cognitive decline and dementia. Epidemiological studies show that consumption of dairy products reduces the risk for cognitive decline and dementia in the elderly. We have previously demonstrated in randomized trials that the consumption of ß-lactolin, a whey-derived Gly-Thr-Trp-Tyr lactotetrapeptide, improves cognitive function in older adults. Orally administered ß-lactolin is delivered to the brain and inhibits monoamine oxidase, resulting in alleviation of memory impairment. However, there is currently no evidence of the effects of long-term ß-lactolin intake on aging. Here, we found that the discrimination index in the novel object recognition test for object recognition memory was reduced in mice aged 20 months compared with that in young mice, indicating that age-related cognitive decline was induced in the aged mice; in aged mice fed ß-lactolin for 3 months, memory impairment was subsequently alleviated. In aged mice, impairment of light/dark activity cycles was found to be induced, which was subsequently alleviated by ß-lactolin consumption. Additionally, the number of activated microglia in the hippocampus and cortex and the production of cytokines (tumor necrosis factor-α, macrophage inflammatory protein-1α, and macrophage chemoattractant protein-1) were increased in aged mice compared with those in young mice but were reduced in aged mice fed ß-lactolin. The age-related hippocampal atrophy was improved in aged mice fed ß-lactolin. Cytochrome c levels in the hippocampus and cortex were increased in aged mice compared with those in young mice but were also reduced by ß-lactolin consumption. These results suggest that ß-lactolin consumption prevents neural inflammation and alleviates aging-related cognitive decline.

Deposition of Phosphorylated α-Synuclein and Activation of GSK-3ß and PP2A in the PS19 Mouse Model of Tauopathy.

The simultaneous accumulation of multiple pathological proteins, such as hyperphosphorylated tau (hp-tau) and phosphorylated α-synuclein (p-αSyn), has been reported in the brains of patients with various neurodegenerative diseases. We previously demonstrated that hp-tau-dependent p-αSyn accumulation was associated with the activation of GSK-3ß in the brains of P301L tau transgenic mice. To confirm the effects of another mutant tau on p-αSyn accumulation in vivo, we herein examined the brains of PS19 mice that overexpress human P301S mutant tau. Immunohistochemically, hp-tau and p-αSyn aggregates were detected in the same neuronal cells in the cerebrum and brain stem of aged PS19 mice. A semiquantitative analysis showed a positive correlation between hp-tau and p-αSyn accumulation. Furthermore, an activated form of GSK-3ß was detected within cells containing both hp-tau and p-αSyn aggregates in PS19 mice. Western blotting showed a decrease in inactivated PP2A levels in PS19 mice. The present results suggest that the overexpression of human P301S mutant tau induces p-αSyn accumulation that is accompanied by not only GSK-3ß, but also PP2A activation in PS19 mice, and highlight the synergic effects between tau and αSyn in the pathophysiology of neurodegenerative diseases that show the codeposition of tau and αSyn.

ß-Lactolin Enhances Neural Activity, Indicated by Event-Related P300 Amplitude, in Healthy Adults: A Randomized Controlled Trial.

BACKGROUND: Epidemiological studies have shown that dairy product consumption is beneficial for cognitive function in elderly individuals. ß-lactolin is a Gly-Thr-Trp-Tyr lacto-tetrapeptide rich in fermented dairy products that improves memory retrieval, attention, and executive function in older adults with subjective cognitive decline and prevents the pathology of Alzheimer's disease in rodents. There has been no study on the effects of ß-lactolin on neural activity in humans. OBJECTIVE: We investigated the effects of ß-lactolin on neural activity and cognitive function in healthy adults. METHODS: In this randomized, double-blind, placebo-controlled study, 30 participants (45-64 years old) consumed ß-lactolin or placebo for 6 weeks. Neural activity during auditory and language tasks was measured through 64-channel electroencephalography. Moreover, verbal fluency tests were performed at baseline and after 6 weeks. RESULTS: The ß-lactolin group had a significantly higher P300 amplitude at the Cp2 site (a part of the parietal lobe near the center of brain, p = 0.011), and C4 site (the area between the frontal and parietal lobe, p = 0.02) during the auditory tasks after 6 weeks than the placebo group. Thus, ß-lactolin supplementation promoted neural activity in the parietal area, which increases concentration and attention during auditory cognitive tasks. Compared with the placebo group, the ß-lactolin group also showed significant changes in the scores of verbal fluency test after 6 weeks (p = 0.033). CONCLUSION: Our findings provide insight into the mechanisms underlying the effects of ß-lactolin on attention in healthy adults.

Effects of ß-Lactolin on Regional Cerebral Blood Flow within the Dorsolateral Prefrontal Cortex during Working Memory Task in Healthy Adults: A Randomized Controlled Trial.

Epidemiological studies have reported that consumption of dairy products rich in ß-lactolin is beneficial for cognitive decline among elderly individuals. Although previous studies have shown that ß-lactolin supplementation improves memory function and attention in healthy adults, the mechanism through which ß-lactolin affects human brain function has yet to be elucidated. This placebo-controlled randomized double-blind study therefore examined the effects of ß-lactolin on human regional cerebral blood flow (rCBF) using near-infrared spectroscopy (NIRS) according to the Consolidated Standards of Reporting Trials guidelines. A total of 114 healthy participants aged between 50 and 75 years with relatively low cognition were randomly allocated into the ß-lactolin or placebo groups (n = 57 for both groups) and received supplementation for 6 weeks. After the 6 weeks of supplementation, total hemoglobin during cognitive tasks (Kraepelin and 2-back tasks) was measured using two-channel NIRS to determine rCBF. Accordingly, the ß-lactolin group had significantly higher changes in total hemoglobin at the left dorsolateral prefrontal cortex (DLPFC) area measured using the left-side channel during the 2-back tasks (p = 0.027) compared to the placebo group. The present study suggests that ß-lactolin supplementation increases rCBF and DLPFC activity during working memory tasks.

Hop Bitter Acids Increase Hippocampal Dopaminergic Activity in a Mouse Model of Social Defeat Stress.

As daily lifestyle is closely associated with mental illnesses, diet-based preventive approaches are receiving attention. Supplementation with hop bitter acids such as iso-α-acids (IAA) and mature hop bitter acids (MHBA) improves mood states in healthy older adults. However, the underlying mechanism remains unknown. Since acute oral consumption with IAA increases dopamine levels in hippocampus and improves memory impairment via vagal nerve activation, here we investigated the effects of chronic administration of hop bitter acids on the dopaminergic activity associated with emotional disturbance in a mouse model of repeated social defeat stress (R-SDS). Chronic administration of IAA and MHBA significantly increased dopaminergic activity based on the dopamine metabolite to dopamine ratio in the hippocampus and medial prefrontal cortex following R-SDS. Hippocampal dopaminergic activity was inversely correlated with the level of R-SDS-induced social avoidance with or without IAA administration. Therefore, chronic treatment with hop bitter acids enhances stress resilience-related hippocampal dopaminergic activity.

Hop bitter acids containing a ß-carbonyl moiety prevent inflammation-induced cognitive decline via the vagus nerve and noradrenergic system.

The prevention of age-related cognitive decline and dementia is becoming a high priority because of the rapid growth of aging populations. We have previously shown that hop bitter acids such as iso-α-acids (IAAs) and matured hop bitter acids (MHBAs) activate the vagus nerve and improve memory impairment. Moreover, supplements with MHBAs were shown to improve memory retrieval in older adults. However, the underlying mechanisms have not been entirely elucidated. We aimed to investigate the effects of MHBAs and the common ß-tricarbonyl moiety on memory impairment induced by the activation of microglia and the loss of the noradrenergic system. MHBAs and a model compound with ß-tricarbonyl moiety were administered to LPS-inoculated mice and 5 × FAD Alzheimer's disease (AD) model mice, following the evaluation in behavioral tests and microglial activation. To evaluate the association of noradrenaline with MHBAs effects, mice treated with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a noradrenergic neurotoxin that selectively damages noradrenergic projections from the locus coeruleus, were subjected to the behavioral evaluation. MHBAs reduced brain inflammation and improved LPS-induced memory impairment. A model compound possessing the ß-tricarbonyl moiety improved the LPS-induced memory impairment and neuronal loss via the vagus nerve. Additionally, the protective effects of MHBAs on memory impairment were attenuated by noradrenaline depletion using DSP-4. MHBAs suppressed the activation of microglia and improved the memory impairment in 5 × FAD mice, which was also attenuated by noradrenaline depletion. Treatment with MHBAs increased cholecystokinin production from the intestinal cells. Generally, cholecystokinin activates the vagal nerve, which stimulate the noradrenergic neuron in the locus ceruleus. Taken together, our results reveal that food ingredients such as hop bitter acids with a ß-tricarbonyl moiety suppress microglial activation and improve memory impairment induced by inflammation or AD pathology via the activation of the gut-brain axis and noradrenergic system. Supplements with hop bitter acids, including MHBAs, might be a novel approach for the prevention of cognitive decline and dementia.

Bitter taste receptor activation by hop-derived bitter components induces gastrointestinal hormone production in enteroendocrine cells.

Matured hop bitter acids (MHBA) are bitter acid oxides derived from hops, widely consumed as food ingredients to add bitterness and flavor in beers. Previous studies have suggested a potential gut-brain mechanism in which MHBA simulates enteroendocrine cells to produce cholecystokinin (CCK), a gastrointestinal hormone which activates autonomic nerves, resulting in body fat reduction and cognitive improvement; however, the MHBA recognition site on enteroendocrine cells has not been fully elucidated. In this study, we report that MHBA is recognized by specific human and mouse bitter taste receptors (human TAS2R1, 8, 10 and mouse Tas2r119, 130, 105) using a heterologous receptor expression system in human embryonic kidney 293T cells. In addition, knockdown of each of these receptors using siRNA transfection partially but significantly suppressed an MHBA-induced calcium response and CCK production in enteroendocrine cells. Furthermore, blocking one of the essential taste signaling components, transient receptor potential cation channel subfamily M member 5, remarkably inhibited the MHBA-induced calcium response and CCK production in enteroendocrine cells. Our results demonstrate that specific bitter taste receptor activation by MHBA drives downstream calcium response and CCK production in enteroendocrine cells. These findings reveal a mechanism by which food ingredients derived from hops in beer activate the gut-brain axis for the first time.

ß-lactolin increases cerebral blood flow in dorsolateral prefrontal cortex in healthy adults: a randomized controlled trial.

The number of elderly individuals with age-related cognitive decline or dementia is rapidly increasing. Dairy product consumption, including ß-lactolin, is beneficial for their cognitive function. The underlying mechanism of ß-lactolin's effects on human brain activity is yet to be investigated. We examined the ß-lactolin effects on human cerebral blood flow (CBF) using near-infrared spectroscopy (NIRS) in a placebo-controlled randomized double-blind study, which reported according to the CONSORT guidelines. Fifty healthy participants (aged 45-60 years) were randomly allocated into the ß-lactolin or the placebo group (n = 25 each) and supplemented for 6 weeks. During the 6th week, oxy-hemoglobin during the working memory tasks was measured using 34-channels (CHs) NIRS. The changes of oxy-hemoglobin, which represents the CBF, in CH 23 located at the left dorsolateral prefrontal cortex (DLPFC) during the spatial working memory task showed higher statistical significance (false discovery rate (q) = 0.045) in the ß-lactolin than in the placebo group. The oxy-Hb changes in CH23 have a co-relationship with the working memory task reaction time. This clinical trial showed an increase in the CBF in the left DLPFC area during the 6-week ß-lactolin supplementation. This study contributes to elucidating the underlying mechanisms of ß-lactolin on cognitive performance.

Phosphorylation and oligomerization of α-synuclein associated with GSK-3ß activation in the rTg4510 mouse model of tauopathy.

Neurodegenerative diseases are characterized by the accumulation of specific phosphorylated protein aggregates in the brain, such as hyperphosphorylated tau (hp-tau) in tauopathies and phosphorylated α-synuclein (p-αSyn) in α-synucleinopathies. The simultaneous accumulation of different proteins is a common event in many neurodegenerative diseases. We herein describe the detection of the phosphorylation and dimerization of αSyn and activation of GSK-3ß, a major kinase known to phosphorylate tau and αSyn, in the brains of rTg4510 mice that overexpress human P301L mutant tau. Immunohistochemistry showed p-αSyn aggregates in rTg4510 mice, which were suppressed by doxycycline-mediated decreases in mutant tau expression levels. A semi-quantitative analysis revealed a regional correlation between hp-tau and p-αSyn accumulation in rTg4510 mice. Furthermore, proteinase K-resistant αSyn aggregates were found in the region with excessive hp-tau accumulation in rTg4510 mice, and these aggregates were morphologically different from proteinase K-susceptible p-αSyn aggregates. Western blotting revealed decreases in p-αSyn monomers in TBS- and sarkosyl-soluble fractions and increases in ubiquitinated p-αSyn dimers in sarkosyl-soluble and insoluble fractions in rTg4510 mice. Furthermore, an activated form of GSK-3ß was immunohistochemically detected within cells containing both hp-tau and p-αSyn aggregates. A semi-quantitative analysis revealed that increased GSK-3ß activity strongly correlated with hp-tau and p-αSyn accumulation in rTg4510 mice. Collectively, the present results suggest that the overexpression of human P301L mutant tau promoted the phosphorylation and dimerization of endogenous αSyn by activating GSK-3ß in rTg4510 mice. This synergic effect between tau, αSyn, and GSK-3ß may be involved in the pathophysiology of several neurodegenerative diseases that show the accumulation of both tau and αSyn.

Supplementation with Matured Hop Bitter Acids Improves Cognitive Performance and Mood State in Healthy Older Adults with Subjective Cognitive Decline.

BACKGROUND: Prevention of age-related cognitive decline and depression is becoming urgent because of rapid growing aging populations. Effects of vagal nerve activation on brain function by food ingredients are inadequately investigated; matured hop bitter acid (MHBA) administration reportedly improves cognitive function and depression via vagal nerve activation in model mice. OBJECTIVE: We investigated the effects of MHBA supplementation on cognitive function and mood state in healthy older adults with perceived subjective cognitive decline. METHODS: Using a randomized double-blind placebo-controlled trial design, 100 subjects (aged 45-69 years) were randomly assigned into placebo (n = 50) and MHBA (n = 50) groups, and received placebo or MHBA capsules daily for 12 weeks. RESULTS: Symbol Digit Modalities Test (SDMT) score assessing divided attention at week 12 was significantly higher (p = 0.045) and ß-endorphin at week 12 was significantly lower (p = 0.043) in the subjects receiving MHBA. Transthyretin in serum, a putative mild cognitive impairment marker, was significantly higher at week 12 in the MHBA group than in the placebo group (p = 0.048). Subgroup analysis classified by the subjective cognitive decline questionnaire revealed that in addition to improved SDMT scores, memory retrieval assessed using the standard verbal paired-associate learning tests and the Ray Verbal Learning Test at week 12 had significantly improved in the subgroup with perceived subjective cognitive decline and without requirement for medical assistance in the MHBA group compared with that in the placebo group. CONCLUSION: This study suggested that MHBA intake improves cognitive function, attention, and mood state in older adults.

Distillation remnants of shochu, a traditional Japanese liquor, improve pork meat quality by reducing stress.

Distillation remnants of Shochu, a traditional Japanese liquorare fed to livestock, but their effects on livestock health have not been investigated. Here, we investigated the effects of these remnants on pig stress and pork quality (N = 6/group). The remnants reduced plasma cortisol (17.94 ± 0.92 [control] and 10.59 ± 1.28 [sample]) and increased salivary IgA (6.06 ± 2.21 [control] and 21.60 ± 5.37 [sample]). Blind sensory assessments showed that, in remnant-fed pork, sirloin tenderness (3.18 ± 0.19 [control] and 4.27 ± 0.38 [sample]) and the juiciness, umami, and fat tastiness of fillets were improved. Oleic acid percentages were higher (35.23 ± 0.65 [control] and 37.87 ± 0.60 [sample]) in remnant-fed pork, contributing to a favorable sensory evaluation. Two-group comparisons were analyzed by student's t test. p < 0.05. This study promotes the reutilization of remnants to reduce livestock stress and improve meat quality.

Amyloid ß-induced Mesenteric Inflammation in an Alzheimer's Disease Transgenic Mouse Model.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder histopathologically characterized by the accumulation of amyloid ß (Aß) peptides and inflammation associated with activated microglia. These features are well investigated in the central nervous system using AD-model mice; however, peripheral inflammation in these mice has not been investigated well. OBJECTIVE: We evaluated the inflammatory responses, especially myeloid dendritic cells (mDCs), in peripheral lymphoid tissues in AD-model mice to determine their association with Aß deposition. METHODS: We collected lymphocytes from mesenteric lymphoid nodes (MLNs) and Peyer's patches (PPs) of 5×FAD transgenic mice used as an AD model. Lymphocytes were analyzed using a flow cytometer to characterize mDCs and T cells. Collected lymphocytes were treated with Aß1-42 ex vivo to evaluate the inflammatory response. RESULTS: We observed elevated levels of inflammatory cytokines and chemokines including interleukin (IL)-12 and macrophage inflammatory protein-1α in mDCs from MLNs and PPs and reduced levels of programmed death-ligand-1, an immunosuppressive co-stimulatory molecule, on the surface of mDCs from 5×FAD mice. Additionally, we found increases in interferon (IFN)-γ-producing CD4- or CD8- positive T cells in MLNs were increased in 5×FAD mice. Moreover, ex vivo treatment with Aß peptides increased the production of IL-12 and IFN-γ by lymphocytes from 5×FAD mice. CONCLUSION: The present study showed that pro-inflammatory mDC and T cells were induced in MLNs and PPs of 5×FAD mice.

ß-Lactolin, a Whey-Derived Lacto-Tetrapeptide, Prevents Alzheimer's Disease Pathologies and Cognitive Decline.

The prevention of age-related memory decline and dementia has been becoming a high priority because of the rapid growth in aging populations. Accumulating epidemiological and clinical studies indicate that intake of fermented dairy products rich in ß-lactolin improves memory retrieval and executive function and attenuates cognitive decline in the elderly. However, the effects of long-term consumption of ß-lactolin on Alzheimer's disease (AD) pathologies have not been investigated. In the present study, we examined the effects of ß-lactolin and whey digestion rich in ß-lactolin on AD pathology in 5×FAD transgenic mice and PS19 tauopathy mice. Intake of ß-lactolin and whey digestion rich in ß-lactolin reduced the levels of inflammatory cytokines, suppressed the infiltration of activated microglia, decreased the levels of amyloid-ß, ameliorated impaired long-term object memory, and attenuated decreased synaptophysin, dopamine, brain-derived neurotrophic factor, and insulin-like growth factor 1 levels in the cortex in 5×FAD transgenic mice. In addition, intake of ß-lactolin and whey digestion rich in ß-lactolin improved behavioral abnormality and reduced the ratio of phosphorylated tau to total tau in the cortex in PS19 tauopathy mice. These findings indicate that consumption with ß-lactolin and whey digestion rich in ß-lactolin suppresses inflammation and attenuates AD pathology and cognitive impairment.

Improving Effects of Hop-Derived Bitter Acids in Beer on Cognitive Functions: A New Strategy for Vagus Nerve Stimulation.

Dementia and cognitive decline are global public health problems. Moderate consumption of alcoholic beverages reduces the risk of dementia and cognitive decline. For instance, resveratrol, a polyphenolic compound found in red wine, has been well studied and reported to prevent dementia and cognitive decline. However, the effects of specific beer constituents on cognitive function have not been investigated in as much detail. In the present review, we discuss the latest reports on the effects and underlying mechanisms of hop-derived bitter acids found in beer. Iso-α-acids (IAAs), the main bitter components of beer, enhance hippocampus-dependent memory and prefrontal cortex-associated cognitive function via dopamine neurotransmission activation. Matured hop bitter acids (MHBAs), oxidized components with ß-carbonyl moieties derived from aged hops, also enhance memory functions via norepinephrine neurotransmission-mediated mechanisms. Furthermore, the effects of both IAAs and MHBAs are attenuated by vagotomy, suggesting that these bitter acids enhance cognitive function via vagus nerve stimulation. Moreover, supplementation with IAAs attenuates neuroinflammation and cognitive impairments in various rodent models of neurodegeneration including Alzheimer's disease. Daily supplementation with hop-derived bitter acids (e.g., 35 mg/day of MHBAs) may be a safe and effective strategy to stimulate the vagus nerve and thus enhance cognitive function.

ß-lactolin, a whey-derived glycine-threonine-tryptophan-tyrosine lactotetrapeptide, improves prefrontal cortex-associated reversal learning in mice.

Dementia and cognitive decline have become worldwide public health problems. We have previously reported that a whey-derived glycine-threonine-tryptophan-tyrosine peptide, ß-lactolin, improves hippocampus-dependent memory functions in mice. The supplementation with a whey digest rich in ß-lactolin improves memory retrieval and executive function in a clinical trial, but the effect of ß-lactolin on prefrontal cortex (PFC)-associated cognitive function was unclear. Here we examined the effect of ß-lactolin and the whey digest on PFC-associated visual discrimination (VD) and reversal discrimination (RD) learning, using a rodent touch panel-based operant system. ß-Lactolin and the whey digest significantly improved the RD learning, and the whey digest enhanced the response latency during the VD task, indicating that ß-lactolin and the whey digest improve PFC-associated cognitive functions. Given the translational advantages of the touch panel operant system, consumption of ß-lactolin in daily life could be beneficial for improving human PFC-associated cognitive function, helping to prevent dementia.

Effect of Microglial Inflammation in Prion Disease.

Prion diseases are a group of transmissible fatal neurodegenerative disorders. Neuropatho- logical features of prion diseases include neuroinflammation featuring the infiltration of activated microglia in affected brain areas as well as the accumulation of an abnormal isoform of the cellular prion protein and neuronal loss. Recent studies have elucidated that inflammation in the brain induced by microglia plays an important role in the pathogenesis of neurodegenerative disorders including prion disease. Thus, the regulation of neuroin- flammation is key in terms of therapeutic and preventative approaches. The functions of neuroinflammation and microglia in this disease are discussed in this article.