Alongside the rapid growth in aging populations, prevention of age-related memory decline and dementia has become a high priority. Several epidemiological and clinical studies have concluded that fermented dairy products can help to prevent cognitive decline; furthermore, intake of Camembert cheese prevents Alzheimer's pathology in model mice. To elucidate molecular mechanisms underlying the preventive effects of fermented dairy products, here we screened peptides from digested fermented dairy products for ability to improve memory function in a scopolamine-induced amnesia mouse model. We found that Trp-Tyr (WY)-containing peptides from whey protein improved memory function in the mice, and the effects were confirmed in aged mice. The WY-containing peptides directly inhibited monoamine oxidase-B activity and increased dopamine levels in brain tissue. Pretreatment with dopamine receptor antagonist abolished the improvement in memory function due to WY-containing peptides. These results suggest that WY-containing peptides in fermented dairy products increase monoamine levels by inhibiting monoamine oxidase-B activity, helping to prevent age-related 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 ␤-lactolin improves memory retrieval and executive function and attenuates cognitive decline in the elderly. However, the effects of long-term consumption of ␤-lactolin on Alzheimer's disease (AD) pathologies have not been investigated. In the present study, we examined the effects of ␤-lactolin and whey digestion rich in ␤-lactolin on AD pathology in 5 × FAD transgenic mice and PS19 tauopathy mice. Intake of ␤-lactolin and whey digestion rich in ␤lactolin reduced the levels of inflammatory cytokines, suppressed the infiltration of activated microglia, decreased the levels of amyloid-␤, ameliorated impaired long-term object memory, and attenuated decreased synaptophysin, dopamine, brainderived neurotrophic factor, and insulin-like growth factor 1 levels in the cortex in 5 × FAD transgenic mice. In addition, intake of ␤-lactolin and whey digestion rich in ␤-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 ␤-lactolin and whey digestion rich in ␤-lactolin suppresses inflammation and attenuates AD pathology and cognitive impairment.

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) as senile plaques and cerebral amyloid angiopathy, and hyperphosphorylated tau (hp-tau) as neurofibrillary tangles in the brain. The AD-related pathology has been reported in several non-human animals, and most animals develop only the Aβ or tau pathology. We herein describe the Aβ and hp-tau pathology in the brains of aged pinniped species (seal, sea lion, and walrus). Molecular analyses revealed that the sequence of pinniped Aβ was identical to that of human Aβ. Histopathological examinations detected argyrophilic plaques composed of Aβ associated with dystrophic neurites in the cerebral cortex of aged pinnipeds. Astrogliosis and microglial infiltration were identified around Aβ plaques. Aβ deposits were observed in the blood vessel walls of the meninges and cerebrum. Pinniped tau protein was physiologically subjected to alternative splicing at exons 2, 3, and 10, and presented as five isoforms: two 3-repeat tau isoforms (1N3R, 2N3R) and three 4-repeat tau isoforms (0N4R, 1N4R, 2N4R); 0N3R tau isoform was absent. Histopathological examinations revealed argyrophilic fibrillar aggregates composed of hp-tau in the neuronal somata and neurites of aged pinniped brains. Few hp-tau aggregates were found in oligodendrocytes and microglia. Biochemically, hp-tau of the 3-repeat and 4-repeat isoforms was detected in brain sarkosyl-insoluble fractions. Aβ and hp-tau both predominantly accumulated in the neocortex, particularly the frontal cortex. Furthermore, the activation of GSK-3β was detected within cells containing hp-tau aggregates, and activated GSK-3β was strongly expressed in cases with severe hp-tau pathologies. The present results suggest that, in association with Aβ deposition, the activation of GSK-3β contributes to hp-tau accumulation in pinniped brains. Here, we report that pinniped species naturally accumulate Aβ and tau with aging, similar to the human AD pathology.

Background Alzheimer's disease (AD) is a devastating disease that is accompanied by dementia, and its incidence increases with age. However, no interventions have exhibited clear therapeutic effects. We aimed to develop and characterize behavioral tasks that allow the earlier identification of signs preceding dementia that would facilitate the development of preventative and therapeutic interventions for AD. Method To this end, we developed a 3D virtual reality task sensitive to the activity of grid cells in the entorhinal cortex, which is the region that first exhibits neurofibrillary tangles in AD. We investigated path integration (assessed by error distance) in a spatial navigation task sensitive to grid cells in the entorhinal cortex in 177 volunteers without dementia between 20 and 89 years old. Results In each age group, the percentage of subjects showing impaired path integration correlated with the percentage of subjects showing neurofibrillary tangles in the entorhinal cortex (based on previously published autopsy data) (correlation coefficient = 0.96). To confirm the underlying mechanisms, we investigated a tauopathy mouse model (P301S mutant tau-overexpressing mice; PS19 mice) at 6 months of age, which showed a noticeable accumulation of phosphorylated tau only in the entorhinal cortex, associated with impaired path integration without impairments in spatial cognition or novel object recognition. Conclusion These data suggest that path integration deficit is caused by the accumulation of phosphorylated tau in the entorhinal cortex. This method may allow the early identification of individuals who are likely to develop AD.

Due to the growth in aging populations, prevention for cognitive decline and dementia are in great demand. We previously demonstrated that the consumption of iso-α-acids (IAA), the hop-derived bitter compounds in beer, prevents inflammation and Alzheimer’s disease pathology in model mice. However, the effects of iso-α-acids on inflammation induced by other agents aside from amyloid β have not been investigated. In this study, we demonstrated that the consumption of iso-α-acids suppressed microglial inflammation in the frontal cortex of rTg4510 tauopathy mice. In addition, the levels of inflammatory cytokines and chemokines, including IL-1β and MIP-1β, in the frontal cortex of rTg4510 mice were greater than those of wild-type mice, and were reduced in rTg4510 mice fed with iso-α-acids. Flow cytometry analysis demonstrated that the expression of cells producing CD86, CD68, TSPO, MIP-1α, TNF-α, and IL-1β in microglia was increased in rTg4510 mice compared with wild-type mice. Furthermore, the expression of CD86- and MIP-1α-producing cells was reduced in rTg4510 mice administered with iso-α-acids. Moreover, the consumption of iso-α-acids reduced the levels of phosphorylated tau in the frontal cortex. Collectively, these results suggest that the consumption of iso-α-acids prevents the inflammation induced in tauopathy mice. Thus, iso-α-acids may help in preventing inflammation-related brain disorders.

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.

Cerebral amyloid β (Aβ) deposition is a pathological hallmark of Alzheimer's disease (AD). There are several molecular species of Aβ, including Aβ40, Aβ42, and Aβ43, and the pathological roles of Aβ43 have attracted particular attention in recent years.Aβ43 is mainly deposited as senile plaques (SPs) in AD brains, and is known to be more amyloidogenic and neurotoxic than Aβ42 and Aβ40. Aβ40 and Aβ42 deposition have been demonstrated in several animal species, while Aβ43 deposition has not been studied in animals. The brains of sea lions, dogs, and cats exhibit unique age-related Aβ pathologies. In the present study, the deposition patterns of Aβ40, Aβ42, and Aβ43 were examined immunohistochemically in the brains of aged dogs (n=52), sea lions (n=5), and cats (n=17). In dogs, most cerebral amyloid angiopathy (CAA) lesions and primitive SPs were positive for Aβ42, Aβ43, and Aβ40. However, diffuse SPs and capillary CAA lesions were negative for Aβ40. In sea lions, all SPs and most CAA lesions were positive for Aβ42, Aβ43, and Aβ40, while capillary CAA lesions were negative for Aβ40. In cats, Aβ42-immunopositive granular aggregates and arteriole and capillary CAA lesions were positive for Aβ43, but negative for Aβ40. Double-labelling immunohistochemistry revealed the co-localization of Aβ42 and Aβ43. These findings suggest that Aβ43 and Aβ42 are frequently deposited in the brains of Carnivora animals and may play an important role in Aβ pathology.

The accumulation of specific phosphorylated protein aggregates in the brain is a hallmark of severe neurodegenerative disorders. Specifically, hyperphosphorylated tau (hp-tau) accumulates in Alzheimer disease, frontotemporal dementia with Parkinsonism linked to chromosome 17, and progressive supranuclear palsy; furthermore, phosphorylated α-synuclein (p-αSyn) accumulates in Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. Moreover, codeposition of different pathological protein aggregates is common in the brains of individuals with neurodegenerative diseases. In the present report, we describe the detection of p-αSyn aggregates in the brain of rTg4510 mice that overexpress human P301L mutant tau. Immunohistochemistry showed that hp-tau and p-αSyn aggregates were found within the same neuronal cells in rTg4510 mice and increased with age. Moreover, semiquantitative analysis revealed a significant regional correlation between hp-tau and p-αSyn accumulation. These results indicate that endogenous mouse αSyn protein is phosphorylated and accumulates with hp-tau aggregation in neurons and suggest that the overexpression of human P301L mutant tau may enhance endogenous αSyn phosphorylation and aggregation via a similar hyperphosphorylation mechanism in vivo. This synergic effect between tau and αSyn accumulation may exacerbate the pathology of several neurodegenerative disorders that show a cooccurrence of hp-tau and p-αSyn aggregation.