Chihiro Sato

AMPAR Removal Underlies Aβ-Induced Synaptic Depression and Dendritic Spine Loss

Beta amyloid (Abeta), a peptide generated from the amyloid precursor protein (APP) by neurons, is widely believed to underlie the pathophysiology of Alzheimers disease. Recent studies indicate that this peptide can drive loss of surface AMPA and NMDA type glutamate receptors. We now show that Abeta employs signaling pathways of long-term depression (LTD) to drive endocytosis of synaptic AMPA receptors. Synaptic removal of AMPA receptors is necessary and sufficient to produce loss of dendritic spines and synaptic NMDA responses. Our studies indicate the central role played by AMPA receptor trafficking in Abeta-induced modification of synaptic structure and function.

Notch signaling in the regulation of stem cell self-renewal and differentiation.

Stem cells are rare and unique precursor cells that participate in the building and rebuilding of tissues and organs during embryogenesis, postnatal growth, and injury repair. Stem cells are distinctively endowed with the ability to both self-renew and differentiate, such that they can replenish the stem cell pool while continuing to produce the differentiated daughter cells that are essential for tissue function. Stem cell self-renewal/differentiation decisions must be carefully controlled during organogenesis, tissue homeostasis, and regeneration, as failure in stem cell maintenance or activation can lead to progressive tissue wasting, while unchecked self-renewal is a hallmark of many cancers. Here, we review evidence implicating the Notch signaling pathway, an evolutionarily conserved cell fate determinant with widespread roles in a variety of tissues and organisms, as a crucial regulator of stem cell behavior. As discussed below, this pathway plays varied and critical roles at multiple stages of organismal development, in lineage-specific differentiation of pluripotent embryonic stem cells, and in controlling stem cell numbers and activity in the context of age-related tissue degeneration, injury-induced tissue repair, and malignancy.

Presenilin: RIP and beyond

Over the years the presenilins (PSENs), a family of multi-transmembrane domain proteins, have been ascribed a number of diverse potential functions. Recent in vivo evidence has supported the existence of PSEN functions beyond its well-established role in regulated intramembrane proteolysis. In this review, we will briefly discuss the ability of PSEN to modulate cellular signaling pathways through gamma-secretase cleavage of transmembrane proteins. Additionally, we will critically examine the proposed roles of PSEN in the regulation of beta-catenin function, protein trafficking, calcium regulation, and apoptosis.

Aβ42 Overproduction Associated with Structural Changes in the Catalytic Pore of γ-Secretase COMMON EFFECTS OF PEN-2 N-TERMINAL ELONGATION AND FENOFIBRATE

γ-Secretase is an atypical aspartyl protease that cleaves amyloid β-precursor protein to generate Aβ peptides that are causative for Alzheimer disease. γ-Secretase is a multimeric membrane protein complex composed of presenilin (PS), nicastrin, Aph-1, and Pen-2. Pen-2 directly binds to transmembrane domain 4 of PS and confers proteolytic activity on γ-secretase, although the mechanism of activation and its role in catalysis remain unknown. Here we show that an addition of amino acid residues to the N terminus of Pen-2 specifically increases the generation of Aβ42, the longer and more aggregable species of Aβ. The effect of the N-terminal elongation of Pen-2 on Aβ42 generation was independent of the amino acid sequences, the expression system and the presenilin species. In vitro γ-secretase assay revealed that Pen-2 directly affects the Aβ42-generating activity of γ-secretase. The elongation of Pen-2 N terminus caused a reduction in the water accessibility of the luminal side of the catalytic pore of PS1 in a similar manner to that caused by an Aβ42-raising γ-secretase modulator, fenofibrate, as determined by substituted cysteine accessibility method. These data suggest a unique mechanism of Aβ42 overproduction associated with structural changes in the catalytic pore of presenilins caused commonly by the N-terminal elongation of Pen-2 and fenofibrate.

Loss of RBPj in Postnatal Excitatory Neurons Does Not Cause Neurodegeneration or Memory Impairments in Aged Mice

Previous studies suggest that loss of γ-secretase activity in postnatal mouse brains causes age-dependent memory impairment and neurodegeneration. Due to the diverse array of γ-secretase substrates, it remains to be demonstrated whether loss of cleavage of any specific substrate(s) is responsible for these defects. The bulk of the phenotypes observed in mammals deficient for γ-secretase or exposed to γ-secretase inhibitors are caused by the loss of Notch receptor proteolysis. Accordingly, inhibition of Notch signaling is the main cause for untoward effects for γ-secretase inhibitors as therapeutics for Alzheimer’s disease. Therefore, we wished to determine if loss of canonical Notch signaling is responsible for the age-dependent neurodegeneration observed upon γ-secrectase deficiency in the mouse brain. We generated postnatal forebrain-specific RBPj conditional knockout (cKO) mice using the CamKII-Cre driver and examined behavior and brain pathology in 12–18 month old animals. Since all four mammalian Notch receptor homologues signal via this DNA binding protein, these mice lack canonical Notch signaling. We found that loss of RBPj in mature excitatory neurons was well tolerated, with no evidence for neurodegeneration or of learning and memory impairment in mice aged up to 18 months. The only phenotypic deficit we observed in the RBPj-deficient mice was a subtle abnormality in olfactory preferences, particularly in females. We conclude that the loss of canonical Notch signaling through the four receptors is not responsible for age-dependent neurodegeneration or learning and memory deficits seen in γ-secretase deficient mice.

Tau hyperphosphorylation on T217 in cerebrospinal fluid is specifically associated to amyloid-β pathology

Introduction Modification of CSF tau phosphorylation in AD remains controversial since total-tau and phospho-tau levels measured by immunoassays are highly correlated. Methods Stoichiometry of phosphorylation of CSF tau was monitored on five sites by mass spectrometry. We compared 50 participants with AD at mild to moderate stages, others tauopathies and controls then confirmed our results in a cohort of 86 participants cognitively normal or with mild cognitive impairment and stratified according to amyloid-β status. Results Changes in tau phosphorylation rates were observed in AD participants but not in other tauopathies. T181 appeared slightly hyperphosphorylated in AD. In comparison, T217 phosphorylation, was considerably modified. We demonstrated T217 hyperphosphorylation occurred systematically in amyloid positive participants even at preclinical stage (AUC 0.999). T217 phosphorylation change specificity overpasses other phosphorylated tau sites investigated in this study, but also CSF total-tau and p-tau levels. Discussion CSF T217 hyperphosphorylation defines a specific tauopathy status concomitant with ß-amyloidosis.

Erratum: Tau Kinetics in Neurons and the Human Central Nervous System (Neuron (2018) 97(6) (1284–1298.e7)(S0896627318301363)(10.1016/j.neuron.2018.02.015))

Chihiro Sato,* Nicolas R. Barthélemy, Kwasi G. Mawuenyega, Bruce W. Patterson, Brian A. Gordon, Jennifer Jockel-Balsarotti, Melissa Sullivan, Matthew J. Crisp, Tom Kasten, Kristopher M. Kirmess, Nicholas M. Kanaan, Kevin E. Yarasheski, Alaina Baker-Nigh, Tammie L.S. Benzinger, Timothy M. Miller, Celeste M. Karch,* and Randall J. Bateman* *Correspondence: satochihiro@wustl.edu (C.S.), karchc@wustl.edu (C.M.K.), batemanr@wustl.edu (R.J.B.) https://doi.org/10.1016/j.neuron.2018.04.035

MASS SPECTROMETRY–BASED MEASUREMENT OF LONGITUDINAL CSF TAU IDENTIFIES DIFFERENT PHOSPHORYLATED SITES THAT TRACK DISTINCT STAGES OF PRESYMPTOMATIC DOMINANTLY INHERITED AD

exosomes isolated from injected mice contained human tau species as measured by ELISA, suggesting exosome trafficking from the CNS to the periphery. Conclusions: Here, we are the first to demonstrate that secreted exosomes isolated from hiPSCs can propagate human tau and oAb species to multiple brain regions and traffic into the periphery. Our model system provides a means to study transcellular propagation of exosome cargo, and related neurodegenerative mechanisms. Together, our data suggests that exosomes are mediators of AD pathogenesis and can serve as potential targets for AD therapeutics.

Binding Activity of Hsp70 toward Acidic Glycoconjugates: An Unexpected Role of Sugars@@@糖の意外な働き

ウニの受精において,先体反応後の精子細胞膜が卵の 卵膜に接着する過程が存在する(図1).この過程にお いて,卵膜に局在する精子結合タンパク質(SBP)と精 子細胞膜脂質ラフトに濃縮して存在する主要ガングリオ シ ド(Neu5Acα2,8Neu5Acα2,6GlcCerお よ びNeu5Ac α2,6GlcCer)とのシアル酸依存的な結合が,ウニの受精 の成立において極めて重要な役割を果たすことを筆者ら の研究グループが発見した(4).SBPはそのN末端に存在 する属非特異的精子結合ドメインを介して精子ガングリ オシドと結合する.興味深いことに,SBPのガングリオ シド結合ドメインは70-kDa熱ショックタンパク質 (Hsp70)ファミリータンパク質のN末端領域と40~ 60%の相同性を示す(5).このことから,Hsp70ファミ リータンパク質もまた,シアル酸依存的にガングリオシ ドと相互作用する能力をもつのではないかという仮説を 立てるに至った.

Tau kinetics in the human cns

new datasets), increasing our discovery sample to 21,433 cases and 44,340 controls. Methods: All datasets were imputed to a 1000 Genomes reference panel (Phase 1 v3, March 2012) of over 37 million variants, many of which are low-frequency single nucleotide variants (SNV) and indels. Single-variant-based association analysis was conducted adjusting for age, sex and population substructure. Individual datasets were analyzed with the score test for case-control datasets and general estimating equations (with generalized linear mixed model for rare variants) for family-based analyses. Within-study results were meta-analyzed in METAL. Gene-based testing was conducted on summary statistics using VEGAS. Results: Imputation produced approximately nine million high-quality low-frequency variants for analyses. Twenty-five loci were genomewide significant at P 5310-8, including five novel loci. Three of these novel loci are driven by significant low-frequency variants, while two are associations of common intergenic variants between the genes USP6NL and ECHDC3 at Chr10: 10:11720308 (P1⁄42.91x10) and the genes CYYR1 and ADAMTS1 at Chr21: 28,156,856 (P1⁄41.44x10). Previously reported rare and low-frequency variants in TREM2 and SORL1 were also significantly associated, while low-frequency SNVs in the common loci BIN1 (MAF1⁄40.026) and CLU (MAF1⁄40.029) show suggestive significance (P 5310-7). Twelve additional loci produced signals with suggestive significance, seven driven by low-frequency or rare variants and five driven by common variants. Genotyping to confirm imputation quality, and replication genotyping using the Sequenom MassArray are underway. Gene-based analyses identified 13 significantly associated genes (Bonferroni P 2.83x10-6), four of which are novel loci driven by nominally significant low-frequency variants. Conclusions: Using an imputation set with a large number of rare variants we identified several novel candidate loci for LOAD, giving support to the hypothesis that rare and low-frequency variant imputation can identify novel associations with disease.