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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 β-lactopeptides, including β-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 β-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 β-lactolin, may be beneficial for preventing dementia.

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.

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.

Canavan disease is an autosomal recessive leukodystrophy caused by mutations in the gene encoding aspartoacylase (ASPA), which hydrolyses N-acetylaspartate (NAA) to acetate and aspartate. A similar feline neurodegenerative disease associated with a mutation in the ASPA gene is reported herein. Comprehensive clinical, genetic, and pathological analyses were performed on 4 affected cats. Gait disturbance and head tremors initially appeared at 1 to 19 months of age. These cats eventually exhibited dysstasia and seizures and died at 7 to 53 months of age. Magnetic resonance imaging of the brain revealed diffuse symmetrical intensity change of the cerebral cortex, brainstem, and cerebellum. Gas chromatography–mass spectrometry analysis of urine showed significant excretion of NAA. Genetic analysis of the 4 affected cats identified a missense mutation (c.859G>C) in exon 6 of the ASPA gene, which was not detected in 4 neurologically intact cats examined as controls. Postmortem analysis revealed vacuolar changes predominantly distributed in the gray matter of the cerebrum and brain stem as well as in the cerebellar Purkinje cell layer. Immunohistochemically, these vacuoles were surrounded by neurofilaments and sometimes contained MBP- and Olig2-positive cells. Ultrastructurally, a large number of intracytoplasmic vacuoles containing mitochondria and electron-dense granules were detected in the cerebral cortex. All 4 cats were diagnosed as spongy encephalopathy with a mutation in the ASPA gene, a syndrome analogous to human Canavan disease. The histopathological findings suggest that feline ASPA deficiency induces intracytoplasmic edema in neurons and oligodendrocytes, resulting in spongy degeneration of the central nervous system.

A 4-month-old female mixed-breed cat showed gait disturbance and eventual dysstasia with intention tremor and died at 14 months of age. Postmortem histological analysis revealed degeneration of neuronal cells, alveolar epithelial cells, hepatocytes, and renal tubular epithelial cells. Infiltration of macrophages was observed in the nervous system and visceral organs. The cytoplasm of neuronal cells was filled with Luxol fast blue (LFB)-negative and periodic acid-Schiff (PAS)-negative granules, and the cytoplasm of macrophages was LFB-positive and PAS-negative. Ultrastructurally, concentric deposits were observed in the brain and visceral organs. Genetic and biochemical analysis revealed a nonsense mutation (c.1017G>A) in the SMPD1 gene, a decrease of SMPD1 mRNA expression, and reduced acid sphingomyelinase immunoreactivity. Therefore, this cat was diagnosed as having Niemann-Pick disease with a mutation in the SMPD1 gene, a syndrome analogous to human Niemann-Pick disease type A.

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 β-lactolin improves memory retrieval and executive function and attenuates cognitive decline in the elderly. However, the effects of long-term consumption of β-lactolin on Alzheimer’s disease (AD) pathologies have not been investigated. In the present study, we examined the effects of β-lactolin and whey digestion rich in β-lactolin on AD pathology in 5×FAD transgenic mice and PS19 tauopathy mice. Intake of β-lactolin and whey digestion rich in β-lactolin reduced the levels of inflammatory cytokines, suppressed the infiltration of activated microglia, decreased the levels of amyloid-β, 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 β-lactolin and whey digestion rich in β-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 β-lactolin and whey digestion rich in β-lactolin suppresses inflammation and attenuates AD pathology and cognitive impairment.

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-3β 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-3β 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-3β, 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.

Glycogen synthase kinase 3β (GSK-3β) is a therapeutic target for various age-related neurodegenerative diseases. It is linked to the two main pathological features of Alzheimer’s disease (AD), tau and amyloid β (Aβ); GSK-3β is a major candidate to pathologically hyperphosphorylate tau and modulate Aβ production. However, inhibition of GSK-3β in clinical studies in humans has been found to not significantly improve cognitive function of AD patients, prompting us to study the physiological role of GSK-3β in old mice. Using a contextual fear-conditioning paradigm, we now report that old gsk-3β+/− mice are deficient in both short-term and long-term memory formation, suggesting that GSK-3β is required for memory formation at old age. Biochemical and immunohistochemical analyses showed that the number of synapses does not differ between gsk-3β+/− and age-matched wild-type (wt) littermate mice. Based on these observations, we propose that, GSK-3β may contribute to help maintain brain function during aging. Our results may explain the poor efficacy of GSK-3β inhibitors in preserving memory capacity in AD patients.

A 4-month-old female mixed-breed cat showed gait disturbance and eventual dysstasia with intention tremor and died at 14 months of age. Postmortem histological analysis revealed degeneration of neuronal cells, alveolar epithelial cells, hepatocytes, and renal tubular epithelial cells. Infiltration of macrophages was observed in the nervous system and visceral organs. The cytoplasm of neuronal cells was filled with Luxol fast blue (LFB)-negative and periodic acid-Schiff (PAS)-negative granules, and the cytoplasm of macrophages was LFB-positive and PAS-negative. Ultrastructurally, concentric deposits were observed in the brain and visceral organs. Genetic and biochemical analysis revealed a nonsense mutation (c.1017GA) in the

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

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.

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 pressure dependence of superconducting transition temperature $T_{\rm c}$ has been investigated through the DC magnetic measurements for FeSe$_{0.8}$ and FeSe$_{1.0}$. For both samples, with increasing pressure $P$, the $T_{\rm c}$$-$$P$ curve exhibits a two-step increase, showing a local maximum of $\sim$11 K at $P$$\sim$1.0 GPa and a rapid increase with an extremely large pressure coefficient for $P$$>$1.5 GPa. $T_{\rm c}$ saturates at $\sim$25 K (21 K) in FeSe$_{1.0}$ (FeSe$_{0.8}$) for $P$$>$3 GPa. A rapid decrease in superconducting volume fraction is observed with an increase in $T_{\rm c}$ above 1.5 GPa, suggesting the presence of electronic inhomogeneity., 4 pages, 4 figures, to appear in J. Phys. Soc. Jpn, 78 (2009), No. 9

Pressure dependence of superconducting transition temperature $T_{\rm c}$ has been determined through the DC magnetic measurements under pressure up to $P$=10 GPa for $\beta$-pyrochlore oxides AOs$_2$O$_6$ with A=Cs ($T_{\rm c}$=3.3 K), Rb (6.3 K) and K (9.6 K). Both for A=Rb and Cs, $T_{\rm c}$ increases with increasing $P$ and shows a saturation at $T_{\rm cm}$$\sim$8.8 K, which is considered as the upper limit of $T_{\rm c}$ inherent in AOs$_2$O$_6$. In contrast, the $T_{\rm c}-P$ curve for KOs$_2$O$_6$ shows a sharp maximum of $\sim$10 K at $P$$\sim$0.5 GPa, and $T_{\rm c}$ is higher than $T_{\rm cm}$ for 0$\leq$$P$$\leq$1.5GPa, suggesting the enhanced superconductivity due to the rattling of K ions., Comment: 4 pages, 4 figures, to be published in J. Phys. Soc. Jpn. Vol. 77, No. 4 (2008)

DC magnetic measurements have been performed under high pressure for FeSe superconductor (Tc~7 K) for the precise determination of pressure dependence of Tc using miniature diamond anvil cell combined with commercial SQUID magnetometer. FeSe is composed of stacking layers of edge-sharing FeSe4 which is isostructural to the FeAs layers in the new superconductors containing Fe elements such as LaFeAsO1−xFx, Li1−xFeAs, (Ba1−xKx)Fe2As2. It is found that Tc for FeSe increases with increasing pressure P and shows a maximum of Tc~11 K at P~1.0 GPa. Tc is also found to show a rapid increase with an extremely large pressure coefficient for P > 1.5 GPa and then a constant value of Tc~25 K for P > 3.0 GPa. A significant broadening of the superconducting transition is observed with the rapid increase of Tc above 1.5 GPa, suggesting the electronic inhomogeneity.

DC magnetic measurements have been performed for β-pyrochlore superconductor KOs2O6 (Tc = 9.6 K) under pressure for the precise determination of the pressure dependence of Tc, using a miniature diamond anvil cell combined with a commercial SQUID magnetometer. It is found that the critical temperature Tc shows a maximum of ~10 K at P=0.5 GPa. The maximum of Tc is higher than that for CsOs2O6 and RbOs2O6, in both of which Tc is known to increase and saturate at Tcm = 8.8 K by the application of pressure, suggesting the enhanced superconductivity due to the rattling of K ions in an oversized cage of Os-O network. For the further application of pressure, Tc decreases linearly but the decreasing rate appears to be suddenly changed at P~2 GPa and Tc~8 K. The sharp bend of the Tc — P line probably corresponds to the transition concerning to the rattling motion which occurs at Tp=7.5 K at ambient pressure, suggesting the positive pressure dependence of Tp.