Publication

論文

2024

Sun Y, Islam S, Gao Y, Nakamura T, Tomita T, Michikawa M, Zou K: Presenilin deficiency enhances tau phosphorylation and its secretion. J Neurochem. in press. doi: 10.1111/jnc.16155.
Ito G, Tomita T, Utsunomiya-Tate N: Effects of bound nucleotides on the secondary structure, thermal stability, and phosphorylation of Rab3A. Biochem Biophys Res Commun. 723:150199, 2024. doi: 10.1016/j.bbrc.2024.150199.
Etani H, Takatori S, Wang W, Omi J, Akahori A, Watanabe H, Sonn I, Okano H, Hara N, Hasegawa M, Miyashita A, Kikuchi M, Ikeuchi T, Morishima M, Saito Y, Murayama S, Saito T, Saido TC, Takai T, Ohwada T, Aoki J, Tomita T: Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils. bioRxiv. doi: 10.1101/2024.05.08.593262.
Furuta M, Arii S, Umeda H, Matsukawa R, Shizu K, Kaji H, Kawashima SA, Hori Y, Tomita T, Sohma Y, Mitsunuma H, Kanai M: Leuco Ethyl Violet as Self-Activating Prodrug Photocatalyst for In Vivo Amyloid-Selective Oxygenation. Adv Sci. in press. doi: 10.1002/advs.202401346. PMID: 38689504.
Takeda Y, Chinen T, Honda S, Takatori S, Okuada S, Yamamoto S, Fukuyama M, Takeuchi K, Tomita T, Hata S, Kitagawa D: Molecular basis promoting centriole triplet microtubule assembly. Nat Commun. 15(1):2216, 2024. doi: 10.1038/s41467-024-46454-x. PMID: 38519454
Kato Y, Takatori S, Akahori A, Etani H, Chu YN, Tomita T: Protocol for gene knockdown using siRNA in primary cultured neonatal murine microglia. STAR Protocol. 5(1):102867, 2024. doi: 10.1016/j.xpro.2024.102867. PMID: 38341850
Abe T, Kuwahara T, Suenaga S, Sakurai M, Funakawa K, Takatori S, Iwatsubo T: Lysosomal stress drives the release of pathogenic alpha-synuclein from macrophage lineage cells via the LRRK2-Rab10 pathway. iScience 27(2):108893, 2024. doi: 10.1016/j.isci.2024.108893. PMID: 38313055.

2023

Nakamura R, Tomizawa I, Iwai A, Ikeda T, Hirayama K, Chiu YW, Suzuki T, Tarutani A, Mano T, Iwata A, Toda T, Sohma Y, Kanai M, Hori Y, Tomita T: Photo-oxygenation of histidine residue inhibits α-synuclein aggregation. FASEB J 37(12):e23311, 2023. doi: 10.1096/fj.202301533R. PMID: 37962096.
Hayashi Y, Takatori S, Warsame WY, Tomita T, Fujisawa T, Ichijo H: TOLLIP acts as a cargo adaptor to promote lysosomal degradation of aberrant ER membrane proteins. EMBO J 42(23):e114272, 2023. doi: 10.15252/embj.2023114272. Epub 2023 Nov 6. PMID: 37929762.
Atsumi W, Kawabata K, Yamane M, Oi M, Mitsunuma H, Sohma Y, Hori Y, Tomita T, Kanai M: Rose bengal promoted catalytic amyloid-β oxygenation via sono-activation. Synlett in press. doi: 10.1055/a-2182-7614
Tarutani A, Kametani F, Tahira M, Saito Y, Yoshida M, Robinson A, Mann, DMA, Murayama S, Tomita T, Hasegawa M: Distinct tau folds initiate templated seeding and alter the post-translational modification profile. Brain 146(12):4988-4999, 2023. doi: 10.1093/brain/awad272. PMID: 37904205.
Futai E, Kawasaki H, Sato S, Daoudi K, Hidaka M, Tomita T, Ogawa T: A metalloproteinase cocktail from the venom of Protobothrops flavoviridis cleaves amyloid beta peptides at α-cleavage site. Toxins 15(8):500, 2023. doi: 10.3390/toxins15080500. PMID: 37624257.
Umeda H, Sawazaki T, Furuta M, Suzuki T, Kawashima SA, Mitsunuma H, Hori Y, Tomita T, Sohma Y, Kanai M: Quantitative assays for catalytic photo-oxygenation of Alzheimer disease-related tau proteins. ACS Chemical Neurosci. 14(15):2710-2716, 2023. doi: 10.1021/acschemneuro.3c00264. PMID: 37470225.
Kimura T, Sato H, Kano M, Tatsumi L, Tomita T*: Novel aspects of the phosphorylation and structure of pathological tau: implications for tauopathy biomarkers. FEBS Open Bio. in press. doi: 10.1002/2211-5463.13667. PMID: 37391389.
Tarutani A, Lovestam S, Zhang X, Kotecha A, Robinson AC, Mann DMA, Saito Y, Murayama S, Tomita T, Goedert M, Scheres SHW, Hasegawa M: Cryo-EM structures of tau filaments from SH-SY5Y cells seeded with brain extracts from cases of Alzheimer’s disease and corticobasal degeneration. FEBS Open Bio. 13(8):1394-1404, 2023. doi: 10.1002/2211-5463.13657. PMID: 37337995.
Ito G, Tomita T, Utsunomiya-Tate N: LRRK2-mediated phosphorylation and thermal stability of Rab12 are regulated by bound nucleotides. Biochem Biophys Res Commun 667:43-49, 2023. doi: 10.1016/j.bbrc.2023.05.048. PMID: 37207563.
Iwai A, Nakamura R, Tomizawa I, Mitsunuma H, Hori H, Tomita T, Sohma Y*, Kanai M*: Attenuation of α-synuclein aggregation by catalytic photo-oxygenation. Chem Comm 59(38):5745-5748, 2023. doi: 10.1039/d3cc00665d. PMID: 37092686.
Ito K, Araki M, Katai Y, Nishimura Y, Imotani S, Inoue H, Ito G, Tomita T: Pathogenic LRRK2 compromises the subcellular distribution of lysosomes in a Rab12-RILPL1 dependent manner. FASEB J. 37(5):e22930, 2023. doi: 10.1096/fj.202200780RR. PMID: 37086089.
Sato H, Kasuga K, Isoo N, Hayashi T, Ikeuchi T, Hori Y, Tomita T: Soluble form of the APP fragment, sAPPβ, positively regulates tau secretion. Neurosci Res. S0168-0102(23)00068-8. doi: 10.1016/j.neures.2023.03.002. PMID: 36967088.
Chu YN, Akahori A, Takatori S. Tomita T: Pathological roles of INPP5D in Alzheimer disease. Adv Exp Med Biol. 1423:289-301, 2023. doi: 10.1007/978-3-031-31978-5_30. PMID: 37525057.
Iguchi A, Takatori S, Kimura S, Muneto H, Wang K, Etani H, Ito G, Sato H, Hori Y, Sasaki J, Saito T, Saido TC, Ikezu T, Takai T, Sasaki T, Tomita T: INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model. iScience 26(4):106375, 2023. doi: 10.1016/j.isci.2023.106375. PMID: 37035000.
Matsuzaki M, Yokoyama M, Yoshizawa Y, Kaneko N, Naito H, Kobayashi H, Korenaga A, Sekiya S, Ikemura K, Opoku G, Hirohata S, Iwamoto S, Tanaka K, Tomita T: ADAMTS4 is involved in the production of the Alzheimer disease amyloid biomarker APP669-711. Mol. Psychiatry 28(4):1802-1812, 2023. doi: 10.1038/s41380-023-01946-y. PMID: 36721026.
Zou K, Gao Y, Sun Y,Islam S,Nakamura T, Tomita T, Michikawa M: Presenilin 1 deficiency impairs Aβ42-to-Aβ40-and angiotensin-converting activities of ACE. Front. Aging Neurosci. 15:1098034, 2023. doi: 10.3389/fnagi.2023.1098034. PMID: 36875692.
Nasu Y, Kamijo Y, Hashizume R, Sato H, Hori Y, Tomita T, Drobizhev M, Campbell RE: A red fluorescent genetically encoded biosensor for extracellular L-lactate. bioRxiv doi.org/10.1101/2022.08.30.505811.

2022

Nagai-Ito Y, Xu L, Ito K, Kajihara Y, Ito G, Tomita T: The atypical Rab GTPase associated with Parkinson's disease, Rab29, is localized to membranes. J Biol Chem 298(10):102499, 2022. doi: 10.1016/j.jbc.2022.102499. PMID: 36116551.
Hori Y, Sohma Y, Kanai M, Tomita T: Promotion in the Clearance of Aggregated Aβ in vivo using Amyloid Selective Photo-Oxygenation Technology. Neuroscience Insights 17:26331055221126179. doi: 10.1177/26331055221126179. PMID: 36189373.
Tomizawa I, Nakagawa H, Sohma Y, Kanai M, Hori Y, Tomita T: Photo-oxygenation as a new therapeutic strategy for neurodegenerative proteinopathies by enhancing the clearance of amyloid proteins. Front Aging Neurosci 23;14:945017. doi: 10.3389/fnagi.2022.945017. PMID: 35813952.
Yokoyama M, Kobayashi H, Tasumi L, Tomita T: Mouse models of Alzheimer’s diease. Front Mol Neurosci 15: 912995, 2022. doi: 10.3389/fnmol.2022.912995. PMID: 35799899.
Zou K, Islam S, Sun Y, Gao Y, Nakamura T, Komano H, Tomita T, Michikawa M: Presenilin deficiency increases susceptibility to oxidative damage in fibroblasts. Front Aging Neurosci 14:902525, 2022. doi: 10.3389/fnagi.2022.902525
Kaneshiro N, Komai M, Imaoka R, Ikeda A, Kamikubo Y, Saito T, Saido TC, Tomita T, Hashimoto T, Iwatsubo T, Sakurai T, Uehara T, Takasugi N: Lipid flippase dysfunction as a therapeutic target for endosomal anomalies in Alzheimer's disease. iScience. 25(3):103869, 2022. doi: 10.1016/j.isci.2022.103869. PMID: 35243232.
Islam S, Sun Y, Gao Y, Nakamura T, Noorani AA, Li T, Wong PC, Kimura N, Matsubara E, Kasuga K, Ikeuchi T, Tomita T, Zou K, Michikawa M: Presenilin is essential for ApoE secretion, a novel role of presenilin involved in Alzheimer's disease pathogenesis. J Neurosci 42(8):1574-1586, 2022. doi: 10.1523/JNEUROSCI.2039-21.2021. Epub 2022 Jan 5. PMID: 34987110.
Watanabe H, Yoshida C, Hidaka M, Ogawa T, Tomita T, Futai E: Specific Mutations in Aph1 Cause γ-Secretase Activation. Int. J. Mol. Sci. 2022, 23(1), 507. doi.org/10.3390/ijms23010507. PMID: 35008932.

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2021

Ikeda T, Hori Y, Sohma Y, Kanai M, Tomita T: Photo-oxygenation: an innovative new therapeutic approach against amyloidoses. Adv Exp Med Biol. 1339:415-422, 2021. doi: 10.1007/978-3-030-78787-5_52. PMID: 35023134.
Xu L, Nagai Y, Kajihara Y, Ito G, Tomita T: The regulation of Rab GTPases by phosphorylation. Biomolecules. 11(9):1340, 2021. doi: 10.3390/biom11091340. PMID: 34572553.
Hata S, Kikuchi K, Kano K, Saito H, Sobu Y, Saito T, Saido T, Sano Y, Nakaya T, Aoki J, Komano H, Tomita T, Natori S, Suzuki T: Suppression of amyloid β-protein secretion from neurons by cis-9, trans-11-octadecadienoic acid, an isomer of conjugated linoleic acid. J Neurochem 159(3):603-617, 2021. doi: 10.1111/jnc.15490. Epub 2021 Aug 25. PMID: 34379812.
Ito K, Xu L, Ito G, Tomita T*: Detection of Substrate Phosphorylation of LRRK2 in Tissues and Cultured Cells. Methods Mol Biol 2322:53-61, 2021. doi: 10.1007/978-1-0716-1495-2_6. PMID: 34043192.
Kikuchi K, Tatebe T, Sudo Y, Yokoyama M, Kidana K, Chiu YW, Takatori S, Arita M, Hori Y, Tomita T: GPR120 signaling controls amyloid-β degrading activity of matrix metalloproteinases. J Neurosci.41(28):6173-6185, 2021. doi: 10.1523/JNEUROSCI.2595-20.2021. PMID: 34099509.
Fujita Y, Kano K, Kishino S, Nagao T, Shen X, Sato C, Hatakeyama H, Ota Y, Niibori S, Nomura A, Kikuchi K, Yasuno W, Takatori S, Kikuchi K, Sano Y, Tomita T, Suzuki T, Aoki J, Zou K, Natori S, Komano H: Dietary cis-9, trans-11-conjugated linoleic acid reduces amyloid β-protein accumulation and upregulates anti-inflammatory cytokines in an Alzheimer's disease mouse model. Sci Rep. 12;11(1):9749, 2021. doi: 10.1038/s41598-021-88870-9. PMID: 33980877.
Ozawa S, Hori Y, Shimizu Y, Taniguchi A, Suzuki T, Wang W, Chiu YW, Koike R, Yokoshima S, Fukuyama T, Takatori S, Sohma Y, Kanai M, Tomita T: Photo-oxygenation by a biocompatible catalyst reduces amyloid-β levels in Alzheimer’s disease mice. Brain 144(6):1884-1897, 2021. https://doi.org/10.1093/brain/awab058. PMID: 33851209.
Nagashima N, Ozawa S, Furuta M, Oi M, Hori Y, Tomita T, Sohma Y, Kanai M: Catalytic photooxygenation degrades brain Aβ in vivo. Sci. Adv. 7(13): eabc9750, 2021. doi: 10.1126/sciadv.abc9750. PMID: 33762329.
Cai T, Tomita T*:Sequential conformational changes in transmembrane domains of presenilin 1 in Aβ42 downregulation. J Biochem. 170(2):215-227, 2021. doi: 10.1093/jb/mvab033. PMID: 33739423.
Tarutani A, Miyata H, Nonaka T, Hasegawa K, Yoshida M, Saito Y, Murayama S, Robinson AC, Mann DMA, Tomita T, Hasegawa M: Human tauopathy-derived tau strains determine the substrates recruited for templated amplification. Brain. 144(8):2333-2348, 2021. doi: 10.1093/brain/awab091. Online ahead of print. PMID: 33693528.
Araki M, Takatori S, Ito G, Tomita T: BORCS6 is involved in the enlargement of lung lamellar bodies in Lrrk2 knockout mice. Hum Mol Genet, 30(17):1618-1631, 2021, doi: 10.1093/hmg/ddab146. PMID: 34077533.
Watanabe H, Imaizumi K, Cai T, Zhou Z, Tomita T, Okano H: Flexible and Accurate Substrate Processing with Distinct Presenilin/γ-Secretases in Human Cortical Neurons. eNeuro. 8(2):ENEURO.0500-20.2021. doi: 10.1523/ENEURO.0500-20.2021. PMID: 33608391.
Lovestam S, Schweighauser M, Matsubara T, Murayama S, Tomita T, Ando T, Hasegawa K, Yoshida M, Tarutani A, Hasegawa M, Goedert M, Scheres SHW: Seeded assembly in vitro does not replicate the structures of α-synuclein filaments from multiple system atrophy. FEBS Open Bio. 11(4):999-1013, 2021. doi: 10.1002/2211-5463.13110. Online ahead of print. PMID: 33548114.
Pampuscenko K, Morkuniene R, Krasauskas L, Smirnovas V, Tomita T, Borutaite V: Distinct neurotoxic effects of extracellular tau species in primary neuronal-glial cultures. Mol Neurobio. 58(2):658-667. doi: 10.1007/s12035-020-02150-7. PMID: 33001416.

2020

Tamura K, Chiu YW, Shiohara A, Hori Y, Tomita T*: EphA4 regulates Aβ production via BACE1 expression in neurons. FASEB J. 34(12):16383-16396, 2020. doi: 10.1096/fj.202001510R. PMID: 33090569.
Hata S, Kikuchi K, Kano K, Saito H, Sobu Y, Kinoshita S, Saito T, Saido TC, Sano Y, Taru H, Aoki J, Komano H, Tomita T, Natori S, Suzuki T: Suppression of amyloid-β secretion from neurons by cis-9, trans-11-octadecadienoic acid, an isomer of conjugated linoleic acid. Preprint at bioRxiv 2020.09.13.295642; doi: 10.1101/2020.09.13.295642.
Yumoto T, Kimura M, Nagatomo R, Sato T, Utsunomiya S, Aoki N, Kitaura M, Takahashi K, Takemoto H, Watanabe H, Okano H, Yoshida F, Nao Y, Tomita T*: Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms. Mol Autism 11(1):68, 2020. doi: 10.1186/s13229-020-00373-y. PMID: 32873342.
Schweighauser M, Shi Y, Tarutani A, Kametani F, Murzin AG, Ghetti B, Matsubara T, Tomita T, Ando T, Hasegawa K, Murayama S, Yoshida M, Hasegawa M, Scheres SHW, Goedert M: Structures of α-synuclein filaments from multiple system atrophy. Nature 585(7825):464-469, 2020. doi: 10.1038/s41586-020-2317-6. PMID: 32461689.
Chiu YW, Hori Y, Ebinuma I, Sato H, Hara N, Ikeuchi T, Tomita T*: Identification of calcium and integrin-binding protein 1 as a novel regulator of production of amyloid β peptide using CRISPR/Cas9-based screening system. FASEB J. 34(6):7661-7674, 2020. doi: 10.1096/fj.201902966RR. PMID: 32307772.
Cai T, Tomita T*: Structure-activity relationship of presenilin in γ-secretase-mediated intramembrane cleavage. Semin. Cell Dev. Biol. 105:102-109, 2020. pii: S1084-9521(18)30291-X. doi: 10.1016/j.semcdb.2020.02.006. PMID: 32171519.
Zhang W, Tarutani A, Newell KL, Murzin AG, Matsubara T, Falcon B, Vidal R, Garringer HJ, Shi Y, Ikeuchi T, Murayama S, Ghetti B, Hasegawa M, Goedert M, Scheres SHW: Novel tau filament fold in corticobasal degeneration. Nature 580(7802):283-287, 2020. doi: 10.1038/s41586-020-2043-0. PMID: 32050258.
Zhai L, Otani Y, Hori Y, Tomita T, Ohwada T: Peptide-based Short Single β-Strand Mimics Without Hydrogen Bonding or Aggregation. Chem Commun. 56, 1573 -1576, 2020. doi: 10.1039/c9cc08378b. PMID: 31930273.
Cai T, Hatano A, Kanatsu K, Tomita T*: Histidine 131 in presenilin 1 is the pH-sensitive residue that causes the increase in Aβ42 level in acidic pH. J Biochem. 167(5):463-471, 2020. doi: 10.1093/jb/mvz110. PMID: 31816046.

2019

Cai T, Morishima K, Takagi-Niidome S, Tominaga A, Tomita T*: Conformational dynamics of transmembrane domain 3 of presenilin 1 is associated with the trimming activity of γ-secretase. J Neurosci. 39(43), 8600-8610, 2019. DOI: 10.1523/JNEUROSCI.0838-19.2019. PMID: 31527118.
Furusawa K, Takasugi T, Chiu Y-W, Hori Y, Tomita T, Fukuda M, Hisanaga S-i: CD2-associated protein (CD2AP) overexpression accelerates amyloid precursor protein (APP) transfer from early endosomes to the lysosomal degradation pathway. J Biol Chem. 294(28):10886-10899, 2019. doi:10.1074/jbc.RA118.005385.
Suzuki T, Hori Y, Sawazaki T, Shimizu Y, Nemoto Y, Taniguchi A, Ozawa S, Sohma Y*, Kanai M*, Tomita T*: Photo-oxygenation inhibits tau amyloid formation. Chem Commun 55: 6165-6168, 2019. doi: 10.1039/C9CC01728C. PMID: 31049495.
Imai S, Cai T, Yoshida C, Tomita T, Futai E*: Specific mutations in presenilin 1 cause conformational changes in γ-secretase to modulate amyloid beta trimming. J Biochem. 165(1):37-46, 2019. doi: 10.1093/jb/mvy081. PMID: 30289529.
Takatori S, Wang W, Iguchi A, Tomita T*: Genetic Risk Factors for Alzheimer Disease -
Emerging Roles of Microglia in Disease Pathomechanisms. Adv Exp Med Biol.1118:83-116, 2019. doi: 10.1007/978-3-030-05542-4_5. PMID: 30747419.
Brummer T, Muller SA, Pan-Montojo F, Yoshida F, Fellgiebel A, Tomita T, Endres K, Lichtenthaler SF: NrCAM is a marker for substrate-selective activation of ADAM10 in Alzheimer 's disease. EMBO Mol Med. pii: e9695, 2019. doi: 10.15252/emmm.201809695. PMID: 30833305.

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2018

Tsuji T*, Takatori S*, Fujimoto T: Definition of phosphoinositide distribution in the nanoscale. Curr Opin Cell Biol. 57:33-39, 2018. doi: 10.1016/j.ceb.2018.10.008. PMID: 30423517.
Araki M, Ito G*, Tomita T*: Physiological and pathological functions of LRRK2: implications from substrate proteins. Neuronal Signaling. 2(4): NS20180005, 2018. doi: 10.1042/NS20180005.
Eguchi T, Kuwahara T, Sakurai M, Komori T, Fujimoto T, Ito G, Yoshimura S, Harada A, Fukuda M, Koike M, Iwatsubo T: LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis. Proc Natl Acad Sci U S A. 115(39):E9115-E9124, 2018. doi: 10.1073/pnas.1812196115. PMID: 30209220.
Cai T, Tomita T*: Substituted cysteine accessibility method. Bio-protocol 8(17), September 05, 2018. doi: 10.21769/BioProtoc.2470.
Kanatsu K, Hori Y, Ebinuma I, Chiu YW, Tomita T*: Retrograde transport of γ-secretase from endosomes to the trans-Golgi network regulates Aβ42 production. J Neurochem.147(1):110-123, 2018. doi: 10.1111/jnc.14477. PMID: 29851073.
Takatori S, Tomita T*: AP180 N-terminal Homology (ANTH) and Epsin N-terminal Homology (ENTH) Domains: Physiological Functions and Involvement in Disease. Adv Exp Med Biol. in press. doi: 10.1007/5584_2018_218. PMID: 29774507.
Tarutani A, Arai T, Murayama S, Hisanaga SI, Hasegawa M: Potent prion-like behaviors of pathogenic α-synuclein and evaluation of inactivation methods. Acta Neuropathol Commun. 6(1):29, 2018. doi: 10.1186/s40478-018-0532-2. PMID: 29669601.
Ni J, Taniguchi A, Kuninobu Y, Ozawa S, Hori Y, Kuninobu Y, Saito T, Saido TC, Tomita T, Sohma Y, Kanai M: Near-infrared photoactivatable oxygenation catalysts of amyloid protein. Chem 4(4):807-820, 2018. doi: https://doi.org/10.1016/j.chempr.2018.02.008.
Nakamura A, Kaneko N, Villemagne VL, Kato T, Doecke J, Doré V, Fowler C, Li QX, Martins R, Rowe C, Tomita T, Matsuzaki K, Ishii K, Ishii K, Arahata Y, Iwamoto S, Ito K, Tanaka K, Masters CL, Yanagisawa K: High performance plasma Aβ-amyloid biomarkers for Alzheimer’s disease. Nature 554(7691):249-254, 2018. doi: 10.1038/nature25456. PMID: 29420472.
Kidana K, Tatebe T, Ito K, Saito T, Kikuchi K, Takatori S, Ouchi Y, Saido T, Makino M, Akishita M, Iwatsubo T, Hori Y, Tomita T*: Loss of astrocyte-derived kallikrein 7 exacerbates amyloid pathology in Alzheimer disease model mouse. EMBO Mol Med 10(3): e8184, 2018. doi: 10.15252/emmm.201708184. PMID: 29311134.

2017

Fan Y, Howden AJ, Sarhan AR, Lis P, Ito G, Martinez TN, Brockmann K, Gasser T, Alessi DR, Sammler EM: Interrogating Parkinson's disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils. Biochem J. in press. doi: 10.1042/BCJ20170803. PMID: 29127255
Cai T, Yonaga M, Tomita T*: Activation of γ-secretase trimming activity by topological changes of transmembrane domain 1 of presenilin 1. J Neurosci. 37(50):12272-12280, 2017. doi: 10.1523/JNEUROSCI.1628-17.2017. PMID: 29118109
Mano T, Nagata K, Nonaka T, Tarutani A, Imamura T, Hashimoto T, Bannai T, Koshi-Mano K, Tsuchida T, Ohtomo R, Takahashi-Fujigasaki J, Yamashita S, Ohyagi Y, Yamasaki R, Tsuji S, Tamaoka A, Ikeuchi T, Saido TC, Iwatsubo T, Ushijima T, Murayama S, Hasegawa M, Iwata A: Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease. Proc Natl Acad Sci U S A. 114(45):E9645-E9654, 2017. doi: 10.1073/pnas.1707151114. PMID: 29042514
Aktar S, Takatori S, Tsuji T, Orii M, Ohsaki Y, Cheng J, Fujimoto T: A new electron microscopic method to observe the distribution of phosphatidylinositol 3,4-bisphosphate. Acta Histochem Cytochem. 50(5):141-147, 2017. doi: 10.1267/ahc.17025. PMID: 29276316
Ito G*, Tomita T*: An assay for Rab10 phosphorylation detection by LRRK2 activity using SDS-PAGE with a phosphate-binding tag. J Vis Exp (130), e56688, 2017. doi:10.3791/56688
Ito K, Makino M, Okado K, Tomita T: Memantine inhibits β-amyloid aggregation and disassembles preformed β-amyloid aggregates. Biochem Biophys Res Commun. 798:16-25, 2017. doi: 10.1016/j.ejphar.2017.02.001. PMID: 28167259
Tsuji T, Fujimoto M, Tatematsu T, Cheng J, Orii M, Takatori S, Fujimoto T: Niemann-Pick type C proteins promote microautophagy by expanding raft-like membrane domains in the yeast vacuole. eLife. 6. pii: e25960, 2017. doi: 10.7554/eLife.25960. PMID: 28590904
Kikuchi K, Kidana K, Tatebe T, Tomita T*: Dysregulated metabolism of the amyloid-β protein and therapeutic approaches in Alzheimer disease. J Cell Biochem. 118(12):4183-4190, 2017. doi: 10.1002/jcb.26129. PMID: 28488760
Liu CY, Ohki Y, Tomita T, Osawa S, Reed BR, Jagust W, Van Berlo V, Jin L-W, Chui HC, Coppola G, Ringman JM: Two Novel Mutations in the First Transmembrane Domain of Presenilin 1 Cause Young-Onset Alzheimer’s Disease. J Alzheimer Dis. 58(4):1035-1041, 2017. doi: 10.3233/JAD-161203. PMID: 28550247
Sakurai S, Tomita T, Shimizu T, Ohto U: The crystal structure of mouse LC3B in complex with the FYCO1 LIR reveals the importance of the flanking region of the LIR motif. Acta Crystallogr F Struct Biol Commun. 73:130-137, 2017. doi: 10.1107/S2053230X17001911. PMID: 28291748
Ito K, Tatebe T, Suzuki K, Hirayama T, Hayakawa M, Kubo H, Tomita T, Makino M: Memantine reduces the production of amyloid-β peptides through modulation of amyloid precursor protein trafficking. Eur J Pharmacol. 798:16-25, 2017. doi: 10.1016/j.ejphar.2017.02.001. PMID: 28167259
Tomita T*: Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease. Adv Biol Regul. 64:33-38, 2017. doi: 10.1016/j.jbior.2017.01.001. PMID: 28082052
Tomita T*: Probing the structure and function relationships of presenilin by substituted-cysteine accessibility method. Methods Enzymol. 584:185-205, 2017. doi: 10.1016/bs.mie.2016.10.033. PMID: 28065263
Kanatsu K, Tomita T*: Molecular mechanisms of the genetic risk factors in pathogenesis of Alzheimer disease. Front Biosci (Landmark Ed) 22:180-192, 2017. doi:10.2741/4480. PMID: 27814610

2016

Reinhardt S, Grimm MO, Stahlmann C, Hartmann T, Shudo K, Tomita T, Endres K: Rescue of Hypovitaminosis A induces non-amyloidogenic Amyloid Precursor Protein (APP) Processing. Curr Alzheimer Res. 13(11):1277-1289, 2016. PMID: 27335034
Ito G, Katsemonova K, Tonelli F, Lis P, Baptista M, Shpiro N, Duddy G, Wilson S, Ho WL, Ho SL, Reith AD, Alessi DR: Phos-tag analysis of Rab10 phosphorylation by LRRK2: a powerful assay for assessing kinase function and inhibitors. Biochem J. 2016 Jul 29. pii: BCJ20160557. PMID: 27474410
Shinoda T, Shinya N, Ito K, Ishizuka-Katsura Y, Ohsawa N, Terada T, Hirata K, Kawano Y, Yamamoto M, Tomita T, Ishibashi Y, Hirabayashi Y, Kimura-Someya T, Shirouzu M, Yokoyama S: Cell-free methods to produce structurally intact mammalian membrane proteins. Sci Rep. 6, Article number: 30442 (2016) doi: 10.1038/srep30442. PMID: 27465719
Kanatsu K, Tomita T*: Membrane trafficking and proteolytic activity of γ-secretase in Alzheimer disease. Biol Chem. 397(9):827-835, 2016. doi: 10.1515/hsz-2016-0146. PMID: 27390881
Miyagawa T, Ebinuma I, Morohashi Y, Hori Y, Chang MY, Hattori H, Maehara T, Yokoshima S, Fukuyama T, Tsuji S, Iwatsubo T, Prendergast GC, Tomita T*: BIN1 regulates BACE1 intracellular trafficking and amyloid-β production. Hum Mol Genet. 25(14):2948-2958, 2016. pii: ddw146. doi:10.1093/hmg/ddw146 PMID: 27179792
Hayashi Y, Nishimune H, Hozumi K, Saga Y, Harada A, Yuzaki M, Iwatsubo T, Kopan R, Tomita T*: A novel non-canonical Notch signaling regulates expression of synaptic vesicle proteins in excitatory neurons. Sci Rep. 6, Article number: 23969 (2016) doi:10.1038/sre23969. PMID: 27040987
Kanatsu K, Hori Y, Takatori S, Watanabe T, Iwatsubo T, Tomita T*: Partial loss of CALM function reduces Aβ42 production and amyloid deposition in vivo. Hum Mol Genet. 25(18):3988-3997, 2016. doi: 10.1093/hmg/ddw239 pii: ddw239 PMID: 27466196
Ueda N, Yanagisawa K, Tomita T, Kimura N: Retromer and Rab2-dependent trafficking mediate PS1 degradation by proteasomes in endocytic disturbance. J Neurochem. 137(4):647-658, 2016. doi: 10.1111/jnc.13586. PMID: 26896628
Tominaga A, Cai T, Takagi-Niidome S, Iwatsubo T, Tomita T*: Conformational changes in transmembrane domain 4 of presenilin 1 are associated with altered Aβ42 production. J Neurosci. 36(4):1362-1372, 2016. doi: 10.1523/JNEUROSCI.5090-14.2016. PMID: 26818522
Takatori S, Tatematsu T, Cheng J, Matsumoto J, Akano T, Fujimoto T: Phosphatidylinositol 3,5-bisphosphate-rich membrane domains in endosomes and lysosomes. Traffic 17(2):154-167, 2016. doi: 10.1111/tra.12346. PMID: 26563567
Futai E, Osawa S, Cai T, Fujisawa T, Ishiura S, Tomita T: Suppressor Mutations for Presenilin 1 Familial Alzheimer Disease Mutants Modulate γ-Secretase Activities. J Biol Chem. 291(1):435-446, 2016. pii: jbc.M114.629287. PMID: 26559975

2015

Hori Y, Hashimoto T, Nomoto H, Hyman BT, Iwatsubo T: Role of apolipoprotein E in β-amyloidogenesis: isoform-specific effects on protofibril to fibril conversion of Aβ in vitro and brain Aβ deposition in vivo. J Biol Chem. 290(24):15163-74. doi: 10.1074/jbc.M114.622209. Epub 2015 Apr 27. PMID: 25918154
Takagi-Niidome S, Sasaki T, Osawa S, Sato T, Morishima K, Cai T, Iwatsubo T, Tomita T*: Cooperative substrate gating mechanism by hydrophilic loop 1 and C terminus of presenilin 1 in the amyloid-β production. J Neurosci. 35(6):2646-2656, 2015. doi: 10.1523/JNEUROSCI.3164-14.2015. PMID: 25673856
Hori Y, Takeda S, Cho H, Wegmann S, Shoup TM, Takahashi K, Irimia D, Elmaleh DR, Hyman BT, Hudry E: A Food and Drug Administration-approved asthma therapeutic agent impacts amyloid β in the brain in a transgenic model of Alzheimer disease. J Biol Chem. 290(4):1966-1978, 2015. doi: 10.1074/jbc.M114.586602.
Takasugi N, Sasaki T, Shinohara M, Iwatsubo T, Tomita T*: Synthetic ceramide analogues increase Amyloid-β42 production by modulating γ-secretase activity. Biochem Biophys Res Comm. 457(2):194-199, 2015. doi: 10.1016/j.bbrc.2014.12.087. Epub 2014 Dec 27. PMID: 25545059

2014

Takeo K, Tanimura S, Shinoda T, Osawa S, Zahariev IK, Takegami N, Ishizuka-Katsura Y, Shinya N, Takagi-Niidome S, Tominaga A, Ohsawa N, Kimura-Someya T, Shirouzu M, Yokoshima S, Yokoyama S, Fukuyama T, Tomita T*, Iwatsubo T: Allosteric regulation of γ-secretase activity by a phenylimidazole-type γ-secretase modulator. Proc Natl Acad Sci USA. 111(29):10544-10549, 2014. doi: 10.1073/pnas.1402171111. PMID: 25009180
Yonezawa H, Nishiyama Y, Takeo K, Tomita T, Iwatsubo T, Yokoshima S, Fukuyama T: Novel Photocleavable Linker: γ-Thioacetophenone-type Linker. Bioorg Med Chem Lett. 24(13):2831-2833, 2014. doi: 10.1016/j.bmcl.2014.04.104. PMID: 24841630
Ishifune C, Maruyama S, Sasaki Y, Yagita H, Hozumi K, Tomita T, Kishihara K, Yasutomo K: Differentiation of CD11c+CX3CR1+ cells in the small intestine requires Notch signaling. Proc Natl Acad Sci USA. 111(16):5986-5991, 2014. doi: 10.1073/pnas.1401671111. PMID: 24711412
Kanatsu K, Morohashi Y, Suzuki M, Kuroda H, Watanabe T, Tomita T*, Iwatsubo T: Decreased CALM expression reduces Aβ42 to total Aβ through clathrin-mediated endocytosis of γ-secretase. Nat Commun. 5, Article number: 3386, 2014 doi:10.1038/ncomms4386
Ohki Y, Shimada N, Higo T, Tokoshima S, Fukuyama T, Tomita T*, Iwatsubo T: Binding of longer Aβ to transmembrane domain 1 of presenilin 1 impacts on Aβ42 generation. Mol Neurodegener. 9(1):7, 2014. doi: 10.1186/1750-1326-9-7.
Taniguchi A, Sasaki D, Shiohara A, Iwatsubo T, Tomita T, Sohma Y, Kanai M: Attenuated aggregation and neurotoxicity of amyloid-β peptide by catalytic photo-oxidation. Angew Chem Int Ed Engl. 53(5):1382-1385, 2014. doi: 10.1002/anie.201308001.
Li Y, Hsueh-Jeng Lu S, Tsai CJ, Bohm C, Qamar S, Dodd RB, McDonald B, Meadows W, Jeoh A, McLeod A, Chen F, Arimon M, Berezovska O, Hyman BT, Tomita T, Iwatsubo T, Schmitt-Ulms, S, Fraser P, St. George-Hyslop P: Biophysical analysis of reciprocal allosteric interactions between γ-secretase inhibitor and initial substrate binding sites give insight into human presenilin-1 complex function. Structure 22(1):125-135, 2014. doi: 10.1016/j.str.2013.09.018.

2013

Morohashi Y, Tomita T*: Protein trafficking and maturation regulates intramembrane proteolysis. BBA-Biomembranes 1828(12):2855-2861, 2013. doi: 10.1016/j.bbamem.2013.06.001. PMID: 23770323
Tomita T*, Iwatsubo T: Structural biology of presenilins and signal peptide peptidases. J Biol Chem 288(21):14673-14680, 2013
Toyn JH, Rowley A, Matsuoka Y, Tomita T, Imbimbo BP. γ-Secretase Pharmacology: What Pharmacology Will Work for Alzheimer's Disease? Int J Alzheimers Dis. (Editorial) 2013:849128, 2013. doi: 10.1155/2013/849128.
Imamura Y, Umezawa N, Osawa S, Shimada N, Higo T, Yokoshima S, Fukuyama T, Iwatsubo T, Kato N, Tomita T*, Higuchi T: Effect of helical conformation and side-chain structure on γ-secretase inhibition by β-peptide foldamers: Insight into substrate recognition. J Med Chem 56(4):1443?1454, 2013
Takasugi N, Sasaki T, Ebinuma I, Osawa S, Isshiki H, Takeo K, Tomita T*, Iwatsubo T: FTY720/Fingolimod, a sphingosine analogue, reduces amyloid-β production in neurons. PLoS ONE 8(5):e64050, 2013
Hoshi M, Ohki Y, Ito K, Tomita T, Iwatsubo T, Ishimaru Y, Abe K, Asakura T: Experimental detection of proteolytic activity in a signal peptide peptidase of Arabidopsis thaliana. BMC Biochem 14:16, 2013. doi: 10.1186/1471-2091-14-16. PMID: 23829174
Takagi-Niidome S, Osawa S, Tomita T, Iwatsubo T: Inhibition of γ-secretase activity by a monoclonal antibody against the extracellular hydrophilic loop of presenilin 1. Biochemistry 52:61-69, 2013

2012

Suzuki K, Hayashi Y, Nakahara S, Kumazaki H, Prox J, Horiuchi K, Zheng M, Tanimura S, Nishiyama Y, Osawa S, Sehara-Fujisawa A, Saftig P, Yokoshima S, Fukuyama T, Matsuki N, Koyama R, Tomita T, Iwatsubo T: Activity-dependent proteolytic cleavage of neuroligin-1. Neuron 76:410-422, 2012
Takeo K, Watanabe N, Tomita T, Iwatsubo T: Contribution of γ-secretase cofactors to the formation of catalytic pore of presenilin 1. J Biol Chem 287:25834-25843, 2012
Hayashi I, Takatori S, Urano Y, Iwanari H, Osawa S, Morohashi Y, Li T, Wong PC, Chiba S, Kodama T, Hamakubo T, Tomita T, Iwatsubo T: Neutralization of the γ-secretase activity by monoclonal antibody against extracellular domain of nicastrin. Oncogene 31:787-798, 2012

2011

Tomita T, Wong PC: Selectivity to APP cleavage provides hope against Alzheimer's. Alzheimer’s Research & Therapy 3(2):7, 2011
Yonemura Y, Futai E, Yagishita S, Suo S, Tomita T, Iwatsubo T, Ishiura S: Comparison of preselinin1 and presenilin 2 γ-secretase activities using a yeast reconstitution system. J Biol Chem 286:44569-44575, 2011
Ohki Y, Higo T, Uemura K, Shimada N, Osawa S, Berezovska O, Yokoshima S, Fukuyama T, Tomita T, Iwatsubo T: Phenylpiperidine-type γ-secretase modulators target the transmembrane domain 1 of presenilin 1. EMBO J 30:4815-4824, 2011
Miyashita H, Maruyama Y, Isshiki H, Ogura T, Mio K, Sato C, Tomita T, Iwatsubo T: Three-dimensional structure of the signal peptide peptidase. J Biol Chem 286: 26188-26197, 2011
Takasugi N, Sasaki T, Suzuki K, Osawa S, Isshiki H, Hori Y, Shimada N, Higo T, Yokoshima S, Fukuyama T, Lee VM, Trojanowski JQ, Tomita T, Iwatsubo T: BACE1 activity is modulated by cell-associated sphingosine-1-phosphate. J Neurosci 31: 6850-6857, 2011

2010

Takagi S, Tominaga A, Sato C, Tomita T, Iwatsubo T: Participation of transmembrane domain 1 of presenilin 1 in the catalytic pore structure of the γ-secretase. J Neurosci 30: 15943-15950, 2010
Asai M, Iwata N, Tomita T, Iwatsubo T, Ishiura S, Saido TC, Maruyama K: Efficient four-drug cocktail therapy targeting amyloid-β peptide for Alzheimer’s disease. J Neurosci Res 88:3588-3597, 2010
Kurosumi M, Nishio Y, Osawa S, Kobayashi H, Iwatsubo T, Tomita T, Miyachi H: Novel Notch-sparing γ-secretase inhibitors derived from a peroxisome proliferator- activated receptor agonist library. Bioorg Med Chem Lett 20:5282-5285, 2010
Fukumoto H, Takahashi H, Tarui N, Matsui J, Tomita T, Hirode M, Sagayama M, Maeda R, Kawamoto M, Hirai K, Terauchi J, Sakura Y, Kakihana M, Kato K, Iwatsubo T, Miyamoto M: A non-competitive BACE1 inhibitor TAK-070 ameliorates Aβ pathology and behavioral deficits in a mouse model of Alzheimer’s disease. J Neurosci 30:11157-11166, 2010
Watanabe N, Takagi S, Tomita T, Iwatsubo T: Functional analysis of the transmembrane domains of presenilin 1: participation of transmembrane domains 2 and 6 in the formation of initial substrate binding site of γ-secretase. J Biol Chem 285:19738-19746, 2010
Cheung KH, Mei L, Mak DOD, Hayashi I, Iwatsubo T, Kang DE, Foskett JK: Gain of function Alzheimer's disease presenilin regulation of InsP3 receptor modal gating in patient cells and AD mouse neurons. Science Signaling 3:ra22, 2010

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2009

Tomita T: Secretase inhibitors and modulators for Alzheimer’s disease treatment. Expert Rev Neurotherapeutics 5:661-679, 2009
Masuda S, Kumano K, Suzuki T, Tomita T, Iwatsubo T, Natsugari H, Tojo A, Shibutani M, Mitsumori K, Hanazono Y, Ogawa S, Kurokawa M, Chiba S: Dual antitumor mechanisms of Notch signaling inhibitor in a T cell acute lymphoblastic leukemia xenograft model. Cancer Sci 100:2444-2450, 2009
Yokoshima S, Abe Y, Watanabe N, Kita Y, Kan T, Iwatsubo T, Tomita T, Fukuyama T: Development of photoaffinity probes for γ-secretase equipped with a nitrobenzenesulfonamide-type cleavable linker. Bioorg Med Chem Lett 19:6869-6871, 2009
Hayashi I, Takatori S, Urano Y, Iwanari H, Isoo N, Osawa S, Fukuda MA, Kodama T, Hamakubo T, Li T, Wong PC, Tomita T, Iwatsubo T: Single chain variable fragment against Nicastrin inhibits the γ-secretase activity. J Biol Chem 284:27838-27847, 2009
Imamura Y, Watanabe N, Umezawa N, Iwatsubo T, Kato N, Tomita T, Higuchi T: Inhibition of γ-secretase activity by helical β-peptide foldamers. J Am Chem Soc 131:7353-7359, 2009
Cheng H, Vetrivel KS, Drisdel RC, Meckler X, Gong P, Leem JY, Li T, Carter M, Chen Y, Nguyen P, Iwatsubo T, Tomita T, Wong PC, Green WN, Kounnas MZ, Thinakaran G: s-Palmitoylation of γ-secretase subunits nicastrin and Aph-1. J Biol Chem 284:1373-1384, 2009

2008

Tomita T: Peptides inhibiting specific cleaving activities of presenilins. Expert Opin Therap Pat 18:1097-1100, 2008
Tomita T: At the Frontline of Alzheimer’s disease treatment: γ-secretase inhibitor/modulator mechanism. Naunyn-Schmiedeberg Archives of Pharmacology 377:295-300, 2008
Laras Y, Pietrancosta N, Tomita T, Iwatsubo T, Kraus JL: Synthesis and biological activity of N-substituted spiro[benzoxazepine-piperidine] Aβ-peptide production inhibitors. J Enzyme Inhib Med Chem 7:1, 2008
Cheung K-H, Shineman D, Muller M, Cardenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM-Y, Foskett K: Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron 58:871-883, 2008
Sato C, Takagi S, Tomita T, Iwatsubo T: The C-terminal PAL motif and transmembrane domain 9 of presenilin 1 are involved in the formation of the catalytic pore of the γ-secretase. J Neurosci 28: 6264-6271, 2008

2007

Fuwa H, Takahashi Y, Konno Y, Watanabe N, Miyashita H, Sasaki M, Natsugari H, Kan T, Fukuyama T, Tomita T, Iwatsubo T: Divergent synthesis of multifunctional molecular probes to elucidate the enzyme specificity of dipeptidic γ-secretase inhibitors. ACS Chemical Biology 2:408-418, 2007
Kan T, Kita Y, Morohashi Y, Tominari Y, Hosoda S, Tomita T, Natsugari H, Iwatsubo T, Fukuyama T: Convenient synthesis of photoaffinity probes and evaluation of their labeling abilities. Org Lett 9:2055-2058, 2007
Isoo N, Sato C, Miyashita H, Shinohara M, Takasugi N, Morohashi Y, Tsuji S, Tomita T, Iwatsubo T: Aβ42 overproduction associated with structural changes in the catalytic pore of γ-secretase: common effects of Pen-2 amino-terminal elongation and fenofibrate. J Biol Chem 282:12388-12396, 2007

2006

Tomita T, Iwatsubo T: γ-Secretase as a therapeutic target for treatment of Alzheimer's disease. Current Pharmaceutical Design. 12:661-670, 2006
Fuwa H, Kaneko A, Sugimoto Y, Tomita T, Iwatsubo T, Sasaki M: Concise and short synthesis of functionalized 5,6-dihydropyridin-2-ones by means of palladium(0)-catalyzed cross-coupling of ketene aminal phosphates. Heterocycles 70:101-106, 2006
Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R: AMPA-R removal underlies Aβ-induced synaptic depression. Neuron 52:831-843, 2006
Sato C, Morohashi Y, Tomita T, Iwatsubo T: Structure of the catalytic pore of γ-secretase inferred by the accessibility of substituted cysteines. J Neurosci 26: 12081-12088, 2006
Ozaki , Li Y, Kikuchi H, Tomita T, Iwatsubo T, Nakagawara A: The intracellular domain of the amyloid precursor protein (AICD) enhances the p53-mediated apoptosis. Biochem Biophys Res Comm 351:57-63, 2006
Fuwa H, Hiromoto K, Takahashi Y, Yokoshima S, Kan T, Fukuyama T, Iwatsubo T, Tomita T, Natsugari H: Synthesis of biotinylated photoaffinity probes based on arylsulfonamide γ-secretase inhibitors. Bioorganic & Medicinal Chemistry Letters 16:4184-4189, 2006
Tomita T, Tanaka S, Morohashi Y, Iwatsubo T: Presenilin-dependent intramembrane cleavage of ephrin-B1. Molecular Neurodegeneration 1:2 (doi:10.1186/1750-1326-1-2), 2006
186) Garino C, Tomita T, Pietrancosta N, Laras Y, Rosas R, Herbette G, Maigret B, Quelever G, Iwatsubo T, Kraus J-L: Naphthyl and coumarinyl biarylpiperazine derivatives as highly potent human β-secretase inhibitors. Design, synthesis, enzymatic BACE-1 and cell assays. J Med Chem 49:4275-4285, 2006
Takahashi Y, Fuwa H, Kaneko A, Sasaki M, Yokoshima S, Koizumi H, Takebe T, Kan T, Iwatsubo T, Tomita T, Natsugari H, Fukuyama T: Novel γ-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates. Bioorganic & Medicinal Chemistry Letters 16:3813-3816, 2006
Morohashi Y, Kan T, Tominari Y, Fuwa H, Okamura Y, Watanabe N, Sato C, Natsugari H, Fukuyama T, Iwatsubo T, Tomita T: Carboxyl-terminal fragment of presenilin is the molecular target of a dipeptidic γ-secretase-specific inhibitor DAPT. J Biol Chem 281: 14670-14676, 2006
Ogura T, Mio K, Hayashi I, Miyashita H, Fukuda R, Kopan R, Kodama T, Hamakubo T, Iwatsubo T, Tomita T, Sato C: Three-dimensional structure of the γ-secretase complex. Biochem Biophys Res Comm 343: 525-534, 2006

2005

Takeda T, Asahi M, Yamaguchi O, Hikoso S, Nakayama H, Kusakari Y, Kawai M, Higuchi Y, Kashiwase K, Watanabe T, Taniike M, Nakai A, Nishida K, Kurihara S, Donoviel D, Bernstein A, Tomita T, Iwatsubo T, Hori M, Otsu K: Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling. FASEB J 19:2069-2071, 2005
Watanabe N, Tomita T, Sato C, Kitamura T, Morohashi Y, Iwatsubo T: Pen-2 is incorporated into the γ-secretase complex through binding to transmembrane domain 4 of presenilin 1. J Biol Chem 280:41967-41975, 2005
Urano Y, Hayashi I, Isoo N, Reid PC, Shibasaki Y, Noguchi N, Tomita T, Iwatsubo T, Hamakubo T, Kodama T: Association of active γ-secretase complex with lipid rafts. J Lipid Res 46:904-912, 2005
Niimura M, Isoo N, Takasugi N, Tsuruoka M, Tei-Ui K, Saigo K, Morohashi Y, Tomita T, Iwatsubo T: Aph-1 contributes to the stabilization and trafficking of the γ-secretase complex through mechanisms involving inter- and intramolecular interactions. J Biol Chem 280: 12967-12975, 2005

2004

Tomita T, Iwatsubo T: The Inhibition of γ-secretase as a therapeutic approach to Alzheimer’s disease. Drug News & Perspectives. 17:321-325, 2004.
Tomita T, Takasugi N, Tsuruoka M, Niimura M, Hayashi I, Takahashi Y, Morohashi Y, Isoo N, Tanaka S, Sato C, Iwatsubo T: Functional analysis of presenilin complex and γ-secretase activity. Molecular Neurobiology of Alzheimer Disease and Related Disorders. Edited by M. Takeda. Karger Medical and Scientific Publishers. 2004
Hayashi I, Urano Y, Fukuda R, Isoo N, Kodama T, Hamakubo T, Tomita T, Iwatsubo T: Selective reconstitution and recovery of functional γ-secretase complex on budded baculovirus particles. J Biol Chem 279: 38040-38046, 2004
Kan T, Tominari Y, Rikimaru K, Morohashi Y, Natsugari H, Tomita T, Iwatsubo T, Fukuyama T: Parallel synthesis of DAPT derivatives and their γ-secretase-inhibitory activity. Bioorg Med Chem Lett 14:1983-1985, 2004
Fuwa H, Okamura Y, Morohashi Y, Tomita T, Iwatsubo T, Kan T, Fukuyama T, Natsugari H: Highly efficient synthesis of medium-sized lactams via intramolecular Staudinger-aza-Wittig reaction of ω-azido pentafluorophenyl ester: synthesis and biological evaluation of LY411575 analogues. Tetrahedron Letters 45: 2323-396, 2004

2003

Schroeter EH, Ilagan MXG, Brunkan AL, Hecimovic S, Li Y-M, Xu M, Lewis HD, Saxena MT, De Strooper B, Coonrod A, Tomita T, Iwatsubo T, Moore CL, Shearman M, Goate A, Wolfe MS, Kopan R: A presenilin dimer at the core of the γ-secretase enzyme? Insights from parallel analysis of Notch 1 and APP proteolysis. Proc Natl Acad Sci USA 100: 13075-13080, 2003
Kan T, Tominari Y, Morohashi Y, Natsugari H, Tomita T, Iwatsubo T, Fukuyama T: Solid-phase synthesis of photoaffinity probes: highly efficient incorporation of biotin-tag and cross-linking groups. Chem Commun 17:2244-2245, 2003
Abe Y, Kouyama K, Tomita T, Tomita Y, Ban N, Nawa M, Matsuoka M, Niikura T, Aiso S, Kita Y, Iwatsubo T, Nishimoto I: Analysis of neurons created from wild-type and Alzheimer’s mutation knock-in embryonic stem cells by a highly efficient differentiation protocol. J Neurosci 23:8513-8525, 2003
Takahashi Y, Hayashi I, Tominari Y, Rikimaru K, Morohashi Y, Kan T, Natsugari H, Fukuyama T, Tomita T, Iwatsubo T: Sulindac sulfide is a non-competitive γ-secretase inhibitor that preferentially reduces Aβ42 generation. J Biol Chem 278: 18664-18670, 2003
Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R: APP processing and synaptic function. Neuron 37: 925-937, 2003
Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T: The role of presenilin cofactors in the γ-secretase complex. Nature 422:438-441, 2003
Murakami D, Okamoto I, Nagano O, Kawano Y, Tomita T, Iwatsubo T, De Strooper B, Yumoto E, Saya H: Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44. Oncogene 22: 1511-1516, 2003

2002

Iwatsubo T, Tomita T, Watabiki T, Takikawa R, Morohashi Y, Takasugi N: Presenilin and amyloidogenesis: a structure-function relationship study on presenilin 2. Mapping the Progress of Alzheimer’s and Parkinson’s disease. Edited by Y. Mizuno. Kluwer Academic/Plenum Publishers. 2002
Takasugi N, Takahashi Y, Morohashi Y, Tomita T, Iwatsubo T: The mechanism of γ-secretase activities through high molecular weight complex formation of presenilins is conserved in Drosophila melanogaster and mammals. J Biol Chem 277: 50198-50205, 2002
Leem JY, Saura CA, Pietrzik C, Kim S-H, Veselits ML, Christianson J, Wanamaker C, Tomita T, Gasparini L, Iwatsubo T, Xu H, Green WN, Koo E-H, Thinakaran G: A role for presenilin 1 in regulating the delivery of amyloid precursor protein to the cell surface. Neurobiol Dis 11:64-82, 2002
Okochi M, Steiner H, Fukumori A, Tanii H, Tomita T, Tanaka T, Iwatsubo T, Kudo T, Haass C, Takeda M: Presenilins mediate a dual intramembranous γ-secretase cleavage of Notch-1. EMBO J 21:5408-5416, 2002
Tomita T, Katayama R, Takikawa R, Iwatsubo T: Complex N-glycosylated form of nicastrin is stabilized and selectively bound to presenilin fragments. FEBS lett 520:117-121, 2002
Morohashi Y, Hatano N, Ohya S, Takikawa R, Watabiki T, Takasugi N, Imaizumi Y, Tomita T, Iwatsubo T: Molecular cloning and characterization of CALP/KChIP4, a novel EF-hand protein interacting with presenilin 2 and voltage-gated potassium channel subunit Kv4. J Biol Chem 277: 14965-14975, 2002

2001

Tomita T, Watabiki T, Takikawa R, Morohashi Y, Takasugi N, Kopan R, De Strooper B, Iwatsubo T: The first proline of PALP motif at the C terminus of presenilins is obligatory for stabilization, complex formation and γ-secretase activities of presenilins. J Biol Chem 276:33273-33281, 2001
Iwata H, Tomita T, Maruyama K, Iwatsubo T: Subcellular compartment and molecular subdomain of β-amyloid precursor protein relevant to the Aβ42-promoting effects of Alzheimer mutant presenilin 2. J Biol Chem 276: 21678-21685, 2001
Shirotani K, Tsubuki S, Iwata N, Takaki Y, Harigaya W, Maruyama K, Kiryu-Seo S, Kiyama H, Iwata H, Tomita T, Iwatsubo T, Saido TC: Neprilysin degrades both amyloid β peptide 1-40 and 1-42 most effectively among thiorphan- and phosphoramidon-sensitive endopeptidases. J Biol Chem 276: 21895-21901, 2001
Ohya S, Morohashi Y, Muraki K, Tomita T, Watanabe M, Iwatsubo T, Imaizumi Y: Molecular cloning and expression of the novel splice variants of K+ channel-interacting protein 2 (KChI2). Biochem Biophys Res Comm 282:96-102, 2001

2000

Iwatsubo T, Tomita T: Amyloid and presenilins in the pathobiology of Alzheimer’s disease. Neuroscientific Basis of Dementia. Edited by C. Tanaka, Y. Ihara and P.L. McGeer. Birkhauser Verlag AG 2000 pp. 177-181
Takahashi M, Dore S, Ferris CD, Tomita T, Sawa A, Wolosker H, Borchelt DR, Iwatsubo T, Kim S-H, Thinakaran G, Sisodia SS, Snyder SH: Amyloid precursor proteins inhibit heme oxygenase activity and augument neurotoxicity in Alzheimer’s disease. Neuron 28: 461-473, 2000
Saura CA, Tomita T, Soriano S, Takahashi M, Leem J-Y, Honda T, Koo EH, Iwatsubo T, Thinakaran G: The non-conserved hydrophilic loop domain of presenilin is neither required for presenilin endoproteolysis nor enhanced Aβ42 production mediated by FAD-linked PS variants. J Biol Chem 275:17136-17142, 2000
Maruyama K, Usami M, Kametani F, Tomita T, Iwatsubo T, Saido TC, Mori H, Ishiura S: Molecular interactions between presenilin and calpain: Inhibition of m-calpain protease activity by presenilin-1, 2 and cleavage of presenilin-1 by m-calpain. Int J Mol Med 5:269-273, 2000

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1999

Takashima A, Murayama M, Murayama O, Honda T, Tomita T, Iwatsubo T: Association of presenilin 1 and glycogen synthase kinase-3β and its substrate tau. Alzheimer’s Disease and Related Disorders. Edited by K. Iqbal, D.F. Swaab, B. Winbland and H.M. Wisniewski, John Wiley & Sons Ltd., 1999 pp.323-331
Tomita T, Takikawa R, Koyama A, Morohashi Y, Takasugi N, Saido TC, Maruyama K, Iwatsubo T: C terminus of presenilin is required for overproduction of amyloidogenic Aβ42 through stabilization and endoproteolysis of presenilin. J Neurosci 19:10627-10634, 1999
Fukumoto H, Tomita T, Matsunaga H, Ishibashi Y, Saido TC, Iwatsubo T: Primary cultures of neuronal and non-neuronal rat brain cells secrete similar proportions of amyloid b peptides ending at Aβ40 and Aβ42. Neuroreport 10:2965-2969, 1999
Steiner H, Duff K, Capell A, Romig H, Grim MG, Lincoln S, Hardy J, Yu X, Picciano M, Fechteler K, Citron M, Kopan R, Pesold B, Keck S, Baader M, Tomita T, Iwatsubo T, Baumeister R, Haass C: A loss of function mutation of presenilin-2 interferes with amyloid β peptide production and Notch signaling. J Biol Chem 274:28669-28673, 1999
Nishiyama K, Ikezu T, Trapp BD, Ransohoff RM, Tomita T, Iwatsubo T, Kanazawa I, Dekosky ST, Hsiao KK, Lisanti MP, Okamoto T: Caveolin-3 up-regulation activates γ-secretase mediated cleavage of the amyloid precursor protein (APP) in Alzheimer’s disease. J Neurosci 19: 6538-6548, 1999
Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A: Enhancement of amyloid β 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett 265: 61-63, 1999
Saura CA, Tomita T, Davenport F, Harris CL, Iwatsubo T, Thinakaran G: Evidence that intramolecular associations between presenilin domains are obligatory for endoproteolytic processing. J Biol Chem 274: 13818-13823, 1999

1998

Naruse S, Thinakaran G, Luo J-J, Kusiak JW, Tomita T, Iwatsubo T, Qian X, Ginty, DD, Price, DL, Borchelt DR, Wong PC, Sisodia SS: Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron 17:1213-1221, 1998
Tu P-H, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, Nakajo S, Iwatsubo T, Trojanowski JQ, Lee VM-Y: Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α-synuclein. Ann Neurol 44: 415-422, 1998
Tomita T, Tokuhiro S, Hashimoto T, Aiba K, Saido TC, Maruyama K, Iwatsubo T: Molecular dissection of domains in mutant presenilin 2 that mediate overproduction of amyloidogenic forms of amyloid β peptides: Inability of truncated forms of PS2 with familial Alzheimer’s disease mutation to increase secretion of Aβ42. J Biol Chem 273: 21153-21160, 1998
Shinozaki K, Maruyama K, Saido TC, Kume H, Tomita T, Iwatsubo T, Obata K: The presenilin 2 loop domain interacts with the μ-calpain C-terminal region. Int J of Mol Med 1: 797-799, 1998
Oyama F, Sawamura N, Kobayashi K, Morishima-Kawashima M, Kuramochi T, Ito M, Tomita T, Maruyama K, Saido TC, Iwatsubo T, Capell A, Walter J, Grunberg J, Ueyama Y, Haass C, Ihara Y: Mutant presenilin 2 transgenic mouse: effect on an age-dependent increase of amyloid β-protein (Aβ)42 in the brain. J Neurochem 71:313-322, 1998
Baba M, Nakajo S, Tu P-H, Tomita T, Nakaya K, Lee VM-Y, Trojanowski JQ, Iwatsubo T: Aggregation of α-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152: 879-884, 1998
Tokuhiro S, Tomita T, Iwata H, Kosaka T, Saido TC, Maruyama K, Iwatsubo T: The presenilin 1 mutation (M146V) linked to familial Alzheimer’s disease attenuates the neuronal differentiation of NTera 2 cells. Biochem Biophys Res Comm 244: 751-755, 1998
Tomita T, Chang TY, Kodama T, Iwatsubo T: βAPP γ-secretase and SREBP site 2 protease are two different enzymes. Neuroreport 5: 911-913, 1998

1997

Tomita T, Maruyama K*, Saido TC, Kume H, Shinozaki K, Tokuhiro S, Capell A, Walter J, Gruenberg J, Haass C, Iwatsubo T*, Obata K: The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid β protein ending at the 42nd (or 43rd) residue. Proc Natl Acad Sci USA 94:2025-2030, 1997 (*corresponding author)

1996

Maruyama K, Tomita T, Shinozaki K, Kume H, Asada H, Saido TC, Ishiura S, Iwatsubo T, Obata K: Familial Alzheimer's disease-linked mutations at Val717 of amyloid precursor protein are specific for the increased secretion of Aβ42(43). Biochem Biophys Res Comm 227:730-735, 1996
Kume H, Maruyama K, Tomita T, Iwatsubo T, Saido TC, Obata K: Molecular cloning of a novel basic helix-loop-helix protein from rat brain. Biochem Biophys Res Comm 219:526-530, 1996

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