Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse

<p>Abstract</p> <p>Background</p> <p>Several lines of evidence indicate that memory loss represents a synaptic failure caused by soluble amyloid β (Aβ) oligomers. However, the pathological relevance of Aβ oligomers (AβOs) as the trigger of synaptic or neuronal degeneration, and the possible mechanism underlying the neurotoxic action of endogenous AβOs remain to be determined.</p> <p>Results</p> <p>To specifically target toxic AβOs <it>in vivo</it>, monoclonal antibodies (1A9 and 2C3) specific to them were generated using a novel design method. 1A9 and 2C3 specifically recognize soluble AβOs larger than 35-mers and pentamers on Blue native polyacrylamide gel electrophoresis, respectively. Biophysical and structural analysis by atomic force microscopy (AFM) revealed that neurotoxic 1A9 and 2C3 oligomeric conformers displayed non-fibrilar, relatively spherical structure. Of note, such AβOs were taken up by neuroblastoma (SH-SY5Y) cell, resulted in neuronal death. In humans, immunohistochemical analysis employing 1A9 or 2C3 revealed that 1A9 and 2C3 stain intraneuronal granules accumulated in the perikaryon of pyramidal neurons and some diffuse plaques. Fluoro Jade-B binding assay also revealed 1A9- or 2C3-stained neurons, indicating their impending degeneration. In a long-term low-dose prophylactic trial using active 1A9 or 2C3 antibody, we found that passive immunization protected a mouse model of Alzheimer's disease (AD) from memory deficits, synaptic degeneration, promotion of intraneuronal AβOs, and neuronal degeneration. Because the primary antitoxic action of 1A9 and 2C3 occurs outside neurons, our results suggest that extracellular AβOs initiate the AD toxic process and intraneuronal AβOs may worsen neuronal degeneration and memory loss.</p> <p>Conclusion</p> <p>Now, we have evidence that HMW-AβOs are among the earliest manifestation of the AD toxic process in mice and humans. We are certain that our studies move us closer to our goal of finding a therapeutic target and/or confirming the relevance of our therapeutic strategy.</p

Forebrain Ptf1a Is Required for Sexual Differentiation of the Brain

The mammalian brain undergoes sexual differentiation by gonadal hormones during the perinatal critical period. However, the machinery at earlier stages has not been well studied. We found that Ptf1a is expressed in certain neuroepithelial cells and immature neurons around the third ventricle that give rise to various neurons in several hypothalamic nuclei. We show that conditional Ptf1a-deficient mice (Ptf1a cKO) exhibit abnormalities in sex-biased behaviors and reproductive organs in both sexes. Gonadal hormone administration to gonadectomized animals revealed that the abnormal behavior is caused by disorganized sexual development of the knockout brain. Accordingly, expression of sex-biased genes was severely altered in the cKO hypothalamus. In particular, Kiss1, important for sexual differentiation of the brain, was drastically reduced in the cKO hypothalamus, which may contribute to the observed phenotypes in the Ptf1a cKO. These findings suggest that forebrain Ptf1a is one of the earliest regulators for sexual differentiation of the brain

講義収録装置を用いた授業ライブの学内ネットワーク配信による管理栄養士教育向上に関する取り組み ―学内ネットワークを用いての学生への講義ビデオ配信の試み― 平成23（2011）～25（2013）年度和洋女子大学教育振興支援助成成果報告

本報告は、平成24年・25年度和洋女子大学教育振興支援助成を受けて実施したもので、健康栄養学類での授業における講義収録及び学生への講義ビデオ配信の試みを、その活用実態と学習効果との関連から検討したものである。ここでの講義ビデオとは、講義で用いたパワーポイントデータおよび教員の説明音声と説明ポインター動画を示す。また実習授業収録の場合は、授業中に学生に提示する教員動作動画と説明音声である。　平成24年度に4科目の講義ビデオの配信、平成25年度に10科目の配信を実施した。平成25年度に実施した学生アンケートによって、講義ビデオを活用した学生の人数は科目による差が大きいが、健康栄養学類の1年生は83%、2年生は94%の学生が1年間で1回以上は講義ビデオを活用したことが示された。また、講義ビデオを活用した90%の学生が成績に関係なく、自己の科目理解の向上に有効であったとした。成績と活用状況との関連については、成績Sランクの学生は、その全員が講義ビデオを活用し、すべての回の講義ビデオを活用した者が半数を超えていた。一方低成績者は、講義ビデオを活用しない傾向が高かった。今後、全学的な授業収録・学生配信に向けて、有効かつ活発な活用に向けての環境整備が望まれる

Random Mutagenesis of Presenilin-1 Identifies Novel Mutants Exclusively Generating Long Amyloid β-Peptides

Familial Alzheimer disease-causing mutations in the presenilins increase production of longer pathogenic amyloid beta-peptides (A beta(42/43)) by altering gamma-secretase activity. The mechanism underlying this effect remains unknown, although it has been proposed that heteromeric macromolecular complexes containing presenilins mediate gamma-secretase cleavage of the amyloid beta-precursor protein. Using a random mutagenesis screen of presenilin-1 (PS1) for PS1 endoproteolysis-impairing mutations, we identified five unique mutants, including R278I-PS1 and L435H-PS1, that exclusively generated a high level of A beta43, but did not support physiological PS1 endoproteolysis or A beta40 generation. These mutants did not measurably alter the molecular size or subcellular localization of PS1 complexes. Pharmacological studies indicated that the up-regulation of activity for A beta43 generation by these mutations was not further enhanced by the difluoroketone inhibitor DFK167 and was refractory to inhibition by sulindac sulfide. These results suggest that PS1 mutations can lead to a wide spectrum of changes in the activity and specificity of gamma-secretase and that the effects of PS1 mutations and gamma-secretase inhibitors on the specificity are mediated through a common mechanism.status: publishe

食行為の実態と心身の各種因子との関係について ～ 若年女性と中高年女性の比較による検討 ～

本研究では咀嚼と生活習慣の関係を明らかにするための基礎調査として、まずは、中高年女性で生活習慣に関する背景調査を行い、若年女性と比較を行った。　その結果、生活振り返り調査の「身体の調子・体質」、「ストレス・睡眠」の項目で、グループ間に有意な差が見られた。また、「間食・夜食」、「身体活動」、「健康づくりに対する意識」では若年女性について中高年女性に比較してスコアが低値の傾向が認められた。　今後これらの項目について咀嚼を含む食行為との詳細な検討を行う予定である

女子大生の咀嚼の実態と心身の各種因子との関係について

咀嚼を含めた食行為が女子大生の心身に与える影響を把握するため、マシュマロとチャーハンにおける咀嚼回数の測定並びに、生活習慣および心理状況調査を実施した。また、咀嚼回数の測定と併せて口腔部のサイズや容量、1口の食物投入量、咀嚼数、咀嚼スピード、スプーンの移動回数を測定し、体重や体脂肪量などの各種身体情報の調査も行った。　咀嚼の状況と身体特性との関係性を相関分析により検討したところ、相関関係は確認できなかった。咀嚼の状況と生活習慣との関連の検討において、メタボリックシンドロームに対するリスクと有意な負の相関関係が見られた項目は、スプーン移動回数、チャーハン摂取量、1分あたりの摂取量であった。　以上のように咀嚼の状況と生活習慣および心理状況調査結果との関係については、関連性が示唆される傾向が見られた

230Th/234U chronology of mirabilite from Cape Barne in Ross Island, Antarctica

A ^(Th)/^U method was applied for the dating of a mirabilite collected from Cape Barne in Ross Island, Antarctica. The age of the mirabilite was estimated to be 4700±900y. The ^U/^U activity ratio was 1.23±0.07,which is concordand with the sea water origin of this mineral. Mean uplifting rate of the ground level in the Cape Barne area was estimated to be 5±1mm/y from the ^(Th)/^U age and the altitude of the sampling point