Clinical and Pathological Features of FTDP-17 with MAPT p.K298_H299insQ Mutation.

BACKGROUND: MAPT is a causative gene in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), a hereditary degenerative disease with various clinical manifestations, including progressive supranuclear palsy, corticobasal syndrome, Parkinson's disease, and frontotemporal dementia. OBJECTIVES: To analyze genetically, biochemically, and pathologically multiple members of two families who exhibited various phenotypes of the disease. METHODS: Genetic analysis included linkage analysis, homozygosity haplotyping, and exome sequencing. We conducted tau protein microtubule polymerization assay, heparin-induced tau aggregation, and western blotting with brain lysate from an autopsy case. We also evaluated abnormal tau aggregation by using anti-tau antibody and PM-PBB3. RESULTS: We identified a variant, c.896_897insACA, p.K298_H299insQ, in the MAPT gene of affected patients. Similar to previous reports, most patients presented with atypical parkinsonism. Biochemical analysis revealed that the mutant tau protein had a reduced ability to polymerize microtubules and formed abnormal fibrous aggregates. Pathological study revealed frontotemporal lobe atrophy, midbrain atrophy, depigmentation of the substantia nigra, and four-repeat tau-positive inclusions in the hippocampus, brainstem, and spinal cord neurons. The inclusion bodies also stained positively with PM-PBB3. CONCLUSIONS: This study confirmed that the insACA mutation caused FTDP-17. The affected patients showed symptoms resembling Parkinson's disease initially and symptoms of progressive supranuclear palsy later. Despite the initial clinical diagnosis of frontotemporal dementia in the autopsy case, the spread of lesions could explain the process of progressive supranuclear palsy. The study of more cases in the future will help clarify the common pathogenesis of MAPT mutations or specific pathogeneses of each mutation.

Path integration deficits are associated with phosphorylated tau accumulation in the entorhinal cortex.

Alzheimer's disease 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 behavioural tasks that allow the earlier identification of signs preceding dementia that would facilitate the development of preventative and therapeutic interventions for Alzheimer's disease. 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 Alzheimer's disease. We investigated path integration (assessed by error distance) in a spatial navigation task sensitive to grid cells in the entorhinal cortex in 177 volunteers, aged 20-89 years, who did not have self-reported dementia. While place memory was intact even in old age, path integration deteriorated with increasing age. To investigate the relationship between neurofibrillary tangles in the entorhinal cortex and path integration deficit, we examined a mouse model of tauopathy (P301S mutant tau-overexpressing mice; PS19 mice). At 6 months of age, PS19 mice showed a significant accumulation of phosphorylated tau only in the entorhinal cortex, associated with impaired path integration without impairments in spatial cognition. These data are consistent with the idea 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 likely to develop Alzheimer's disease.

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.

Dendritic distribution of CDK5 mRNA and p35 mRNA, and a glutamate-responsive increase of CDK5/p25 complex contribute to tau hyperphosphorylation.

BACKGROUND: In Alzheimer's disease (AD), abnormally phosphorylated tau in the somatodendrite compartment of brain neurons causes synaptic loss, resulting in neuron death. Although the mechanism by which hyperphosphorylated tau appears in dendrites remains unclear, we have previously reported that local translation of tau mRNA and GSK3ß mRNA in response to glutamatergic stimulation triggers an increase of tau protein and initiation of a cycle for amplification of reactivated preexisting GSK3ß, respectively. In this study, we investigated the mechanism responsible for neural excitation-dependent activation of another major tau kinase, CDK5, within dendrites. METHODS: Primary hippocampal neurons were treated with glutamate and examined by in situ hybridization, immunocytochemistry and Western blotting. RESULTS: The mRNAs for both CDK5 and its neural-specific activator, p35, were found to be constitutively distributed in dendrites. Glutamate treatment induced immediate local dendritic translation of these proteins as well as conversion of p35 to p25, which forms the hyper-activated CDK5/p25 complex. This neural excitation-dependent tau phosphorylation by CDK5 was suppressed in the presence of a calpain inhibitor or a NMDA receptor antagonist. CONCLUSION: Our results indicate that in addition to an increase of dendritic tau and reactivation of preexisting GSK3ß, increase and hyper-activation of CDK5 are evoked by translation of dendrite-distributed mRNAs upon NMDA receptor-mediated neural excitation. GENERAL SIGNIFICANCE: Hyperphosphorylated tau with AD epitopes is locally produced in dendrites via translational activation of dendrite-distributed mRNAs in response to glutamatergic stimulation. Therefore, tau hyperphosphorylation may play a crucial role in synaptic transduction.

Administration of mucuna beans (Mucuna pruriences (L.) DC. var. utilis) improves cognition and neuropathology of 3 × Tg-AD mice.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of extracellular amyloid-beta peptides (Aß) resulting in senile plaques and intracellular hyperphosphorylated tau protein resulting in neurofibrillary tangles (NFTs). Mucuna beans (Mucuna pruriences (L.) DC. var. utilis) are unique plants containing 3-9% L-3,4-dihydroxyphenylalanine (L-DOPA). Here we investigated the effect of the administration of Mucuna beans on AD prevention by feeding triple-transgenic mice (3 × Tg-AD mice) with a diet containing Mucuna beans for 13 months. The levels of Aß oligomers and detergent-insoluble phosphorylated tau decreased in the brain of mice fed with Mucuna beans (Mucuna group) compared to those of the Control group. Aß accumulation and phosphorylated tau accumulation in the brain in the Mucuna group were also reduced. In addition, administration of Mucuna beans improved cognitive function. These results suggest that administration of Mucuna beans may have a preventive effect on AD development in 3 × Tg-AD mice.

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.

Essential roles of plexin-B3+ oligodendrocyte precursor cells in the pathogenesis of Alzheimer's disease.

The role of oligodendrocyte lineage cells, the largest glial population in the adult central nervous system (CNS), in the pathogenesis of Alzheimer's disease (AD) remains elusive. Here, we developed a culture method for adult oligodendrocyte progenitor cells (aOPCs). Fibroblast growth factor 2 (FGF2) promotes survival and proliferation of NG2+ aOPCs in a serum-free defined medium; a subpopulation (~5%) of plexin-B3+ aOPCs was also found. FGF2 withdrawal decreased NG2+, but increased plexin-B3+ aOPCs and Aß1-42 secretion. Plexin-B3+ aOPCs were distributed throughout the adult rat brain, although less densely than NG2+ aOPCs. Spreading depolarization induced delayed cortical plexin-B3+ aOPC gliosis in the ipsilateral remote cortex. Furthermore, extracellular Aß1-42 accumulation was occasionally found around plexin-B3+ aOPCs near the lesions. In AD brains, virtually all cortical SPs were immunostained for plexin-B3, and plexin-B3 levels increased significantly in the Sarkosyl-soluble fractions. These findings suggest that plexin-B3+ aOPCs may play essential roles in AD pathogenesis, as natural Aß-secreting cells.

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.

Disulfide bond formation in microtubule-associated tau protein promotes tau accumulation and toxicity in vivo.

Accumulation of microtubule-associated tau protein is thought to cause neuron loss in a group of neurodegenerative diseases called tauopathies. In diseased brains, tau molecules adopt pathological structures that propagate into insoluble forms with disease-specific patterns. Several types of posttranslational modifications in tau are known to modulate its aggregation propensity in vitro, but their influence on tau accumulation and toxicity at the whole-organism level has not been fully elucidated. Herein, we utilized a series of transgenic Drosophila models to compare systematically the toxicity induced by five tau constructs with mutations or deletions associated with aggregation, including substitutions at seven disease-associated phosphorylation sites (S7A and S7E), deletions of PHF6 and PHF6* sequences (ΔPHF6 and ΔPHF6*), and substitutions of cysteine residues in the microtubule binding repeats (C291/322A). We found that substitutions and deletions resulted in different patterns of neurodegeneration and accumulation, with C291/322A having a dramatic effect on both tau accumulation and neurodegeneration. These cysteines formed disulfide bonds in mouse primary cultured neurons and in the fly retina, and stabilized tau proteins. Additionally, they contributed to tau accumulation under oxidative stress. We also found that each of these cysteine residues contributes to the microtubule polymerization rate and microtubule levels at equilibrium, but none of them affected tau binding to polymerized microtubules. Since tau proteins expressed in the Drosophila retina are mostly present in the early stages of tau filaments self-assembly, our results suggest that disulfide bond formation by these cysteine residues could be attractive therapeutic targets.

Amyloid ß and tau pathology in brains of aged pinniped species (sea lion, seal, and walrus).

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß) 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 Aß or tau pathology. We herein describe the Aß and hp-tau pathology in the brains of aged pinniped species (seal, sea lion, and walrus). Molecular analyses revealed that the sequence of pinniped Aß was identical to that of human Aß. Histopathological examinations detected argyrophilic plaques composed of Aß associated with dystrophic neurites in the cerebral cortex of aged pinnipeds. Astrogliosis and microglial infiltration were identified around Aß plaques. Aß 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. Aß and hp-tau both predominantly accumulated in the neocortex, particularly the frontal cortex. Furthermore, the activation of GSK-3ß was detected within cells containing hp-tau aggregates, and activated GSK-3ß was strongly expressed in cases with severe hp-tau pathologies. The present results suggest that, in association with Aß deposition, the activation of GSK-3ß contributes to hp-tau accumulation in pinniped brains. Here, we report that pinniped species naturally accumulate Aß and tau with aging, similar to the human AD pathology.

Memory formation in old age requires GSK-3ß.

Glycogen synthase kinase 3ß (GSK-3ß) 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 ß (Aß); GSK-3ß is a major candidate to pathologically hyperphosphorylate tau and modulate Aß production. However, inhibition of GSK-3ß 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-3ß in old mice. Using a contextual fear-conditioning paradigm, we now report that old gsk-3ß+/- mice are deficient in both short-term and long-term memory formation, suggesting that GSK-3ß is required for memory formation at old age. Biochemical and immunohistochemical analyses showed that the number of synapses does not differ between gsk-3ß+/- and age-matched wild-type (wt) littermate mice. Based on these observations, we propose that, GSK-3ß may contribute to help maintain brain function during aging. Our results may explain the poor efficacy of GSK-3ß inhibitors in preserving memory capacity in AD patients.

New Insights Into Drug Discovery Targeting Tau Protein.

Microtubule-associated protein tau is characterized by the fact that it is an intrinsically disordered protein due to its lack of a stable conformation and high flexibility. Intracellular inclusions of fibrillar forms of tau with a ß-sheet structure accumulate in the brain of patients with Alzheimer's disease and other tauopathies. Accordingly, detachment of tau from microtubules and transition of tau from a disordered state to an abnormally aggregated state are essential events preceding the onset of tau-related diseases. Many reports have shown that this transition is caused by post-translational modifications, including hyperphosphorylation and acetylation. The misfolded tau is self-assembled and forms a tau oligomer before the appearance of tau inclusions. Animal and pathological studies using human samples have demonstrated that tau oligomer formation contributes to neuronal loss. During the progression of tauopathies, tau seeds are released from cells and incorporated into other cells, leading to the propagation of pathological tau aggregation. Accumulating evidence suggests several potential approaches for blocking tau-mediated toxicity: (1) direct inhibition of pathological tau aggregation and (2) inhibition of tau post-translational modifications that occur prior to pathological tau aggregation, (3) inhibition of tau propagation and (4) stabilization of microtubules. In addition to traditional low-molecular-weight compounds, newer drug discovery approaches such as the development of medium-molecular-weight drugs (peptide- or oligonucleotide-based drugs) and high-molecular-weight drugs (antibody-based drugs) provide alternative pathways to preventing the formation of abnormal tau. Of particular interest are recent studies suggesting that tau droplet formation by liquid-liquid phase separation may be the initial step in aberrant tau aggregation, as well results that implicate roles for tau in dendritic and nuclear functions. Here, we review the mechanisms through which drugs can target tau and consider recent clinical trials for the treatment of tauopathies. In addition, we discuss the utility of these newer strategies and propose future directions for research on tau-targeted therapeutics.

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.

Glutamate-responsive translation of dendritic GSK3ß mRNA triggers a cycle for amplification of reactivated preexisting GSK3ß that is indispensable for tau hyperphosphorylation.

The molecular mechanism responsible for hyperphosphorylated tau accumulation in dendrites of Alzheimer's disease (AD) neurons has not been fully clarified. Recently, we reported that tau mRNA is distributed into dendrites, and that translation and phosphorylation of tau protein are immediately enhanced in response to glutamatergic stimulation. Here, we focused on dendritic glycogen synthase kinase 3ß (GSK3ß), a key enzyme for tau phosphorylation, and investigated the mechanism responsible for the neural stimulation-induced hyperphosphorylation of the newly translated dendritic tau protein. We found that GSK3ß mRNA was also distributed into dendrites of cultured hippocampal neurons, and that a glutamate-dependent slight increase of translation occurred in a short time. Concomitantly, dephosphorylation at the Ser9 residue of the preexisting GSK3ß, which reactivates this kinase, was strongly induced without an increase of its phosphatase PP1 or a decrease of the PP1 inhibitor I-2. Instead, I-2 phosphorylation was observed, suggesting disinhibition of PP1. This glutamate-dependent phosphorylation of I-2 and the dephosphorylation of preexisting GSK3ß were abolished in the presence of GSK3ß inhibitors. Interestingly, translational obstruction of GSK3ß mRNA also canceled these reactions. These results indicate that dendrites exhibit a glutamate-responsive cycle for amplification of reactivated preexisting GSK3ß operating via PP1 disinhibition, whose activation requires neural activity-dependent translation of dendritic GSK3ß mRNA. This would explain why a slight increase of dendritic GSK3ß is sufficient to trigger hyperphosphorylation of significantly increased tau protein.

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.

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.

Enhanced Tau Protein Translation by Hyper-Excitation.

Tau is a microtubule-associated protein, localizing mainly in the axon of mature neurons. Phenotypic analysis of Tau knockout mice has revealed an impairment of synaptic plasticity but without gross changes in brain morphology. Since we previously described the presence of tau mRNA in the somatodendritic compartment, including the postsynapse, and demonstrated that it could be locally translated in response to glutamate, it appears that the regulated translation of synaptic tau can have a direct impact on synaptic function. Using SH-SY5Y cells, we herein confirm that glutamate dose-dependently regulates the translation of tau protein without altering tau mRNA levels. This is supported by the finding that cycloheximide blocks glutamate-stimulated increases in tau protein levels. Our observation that neural excitation can directly upregulate tau mRNA translation helps explain the pathological accumulation of tau in the somatodendrite.

Pathological Progression Induced by the Frontotemporal Dementia-Associated R406W Tau Mutation in Patient-Derived iPSCs.

Mutations in the microtubule-associated protein tau (MAPT) gene are known to cause familial frontotemporal dementia (FTD). The R406W tau mutation is a unique missense mutation whose patients have been reported to exhibit Alzheimer's disease (AD)-like phenotypes rather than the more typical FTD phenotypes. In this study, we established patient-derived induced pluripotent stem cell (iPSC) models to investigate the disease pathology induced by the R406W mutation. We generated iPSCs from patients and established isogenic lines using CRISPR/Cas9. The iPSCs were induced into cerebral organoids, which were dissociated into cortical neurons with high purity. In this neuronal culture, the mutant tau protein exhibited reduced phosphorylation levels and was increasingly fragmented by calpain. Furthermore, the mutant tau protein was mislocalized and the axons of the patient-derived neurons displayed morphological and functional abnormalities, which were rescued by microtubule stabilization. The findings of our study provide mechanistic insight into tau pathology and a potential for therapeutic intervention.