YAP-dependent necrosis occurs in early stages of Alzheimer's disease and regulates mouse model pathology.

Adaptor Proteins, Signal Transducing / metabolism Alzheimer Disease / cerebrospinal fluid Amyloid beta-Peptides / metabolism Animals Cell Cycle Proteins / metabolism Cell Nucleus / metabolism Cognitive Dysfunction / cerebrospinal fluid Computer Simulation Disease Models, Animal Endoplasmic Reticulum / pathology Female HMGB1 Protein / cerebrospinal fluid Humans Induced Pluripotent Stem Cells / metabolism Lysophospholipids / metabolism Male Mice, Transgenic Necrosis Neurons / metabolism Signal Transduction Sphingosine / analogs & derivatives Time-Lapse Imaging Transcription Factors / metabolism YAP-Signaling Proteins

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
24 01 2020
Historique:
received: 01 04 2019
accepted: 19 12 2019
entrez: 26 1 2020
pubmed: 26 1 2020
medline: 9 4 2020
Statut: epublish

Résumé

The timing and characteristics of neuronal death in Alzheimer's disease (AD) remain largely unknown. Here we examine AD mouse models with an original marker, myristoylated alanine-rich C-kinase substrate phosphorylated at serine 46 (pSer46-MARCKS), and reveal an increase of neuronal necrosis during pre-symptomatic phase and a subsequent decrease during symptomatic phase. Postmortem brains of mild cognitive impairment (MCI) rather than symptomatic AD patients reveal a remarkable increase of necrosis. In vivo imaging reveals instability of endoplasmic reticulum (ER) in mouse AD models and genome-edited human AD iPS cell-derived neurons. The level of nuclear Yes-associated protein (YAP) is remarkably decreased in such neurons under AD pathology due to the sequestration into cytoplasmic amyloid beta (Aβ) aggregates, supporting the feature of YAP-dependent necrosis. Suppression of early-stage neuronal death by AAV-YAPdeltaC reduces the later-stage extracellular Aβ burden and cognitive impairment, suggesting that preclinical/prodromal YAP-dependent neuronal necrosis represents a target for AD therapeutics.

Identifiants

DOI: 10.1038/s41467-020-14353-6 PMID: 31980612 PMC: PMC6981281
pubmed: 31980612
doi: 10.1038/s41467-020-14353-6
pii: 10.1038/s41467-020-14353-6
pmc: PMC6981281
doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0
Amyloid beta-Peptides 0
Cell Cycle Proteins 0
HMGB1 Protein 0
Lysophospholipids 0
Transcription Factors 0
YAP-Signaling Proteins 0
YAP1 protein, human 0
Yap1 protein, mouse 0
sphingosine 1-phosphate 26993-30-6
Sphingosine NGZ37HRE42

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

507

Subventions

Organisme : NIA NIH HHS
ID : P01 AG014449
Pays : United States

Références

Doody, R. S., Farlow, M., Aisen, P. S., Alzheimer’s Disease Cooperative Study Data, A. & Publication, C. Phase 3 trials of solanezumab and bapineuzumab for Alzheimer’s disease. N. Engl. J. Med. 370, 1459–1460 (2014).
doi: 10.1056/NEJMoa1312889
Honig, L. S. et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. N. Engl. J. Med. 378, 321–330 (2018).
pubmed: 29365294 doi: 10.1056/NEJMoa1705971 pmcid: 29365294
Doody, R. S. et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med. 369, 341–350 (2013).
pubmed: 23883379 doi: 10.1056/NEJMoa1210951 pmcid: 23883379
Mullard, A. BACE failures lower AD expectations, again. Nat. Rev. Drug Discov. 17, 385 (2018).
pubmed: 29844599 pmcid: 29844599
Sepulcre, J. et al. Neurogenetic contributions to amyloid beta and tau spreading in the human cortex. Nat. Med. 4, 1910–1918 (2018).
doi: 10.1038/s41591-018-0206-4
Sudol, M. Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. Oncogene 9, 2145–2152 (1994).
pubmed: 8035999 pmcid: 8035999
Strano, S. et al. Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J. Biol. Chem. 276, 15164–15173 (2001).
pubmed: 11278685 doi: 10.1074/jbc.M010484200 pmcid: 11278685
Vassilev, A., Kaneko, K. J., Shu, H., Zhao, Y. & DePamphilis, M. L. TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm. Genes Dev. 15, 1229–1241 (2001).
pubmed: 11358867 pmcid: 313800 doi: 10.1101/gad.888601
Huang, J., Wu, S., Barrera, J., Matthews, K. & Pan, D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 122, 421–434 (2005).
pubmed: 16096061 doi: 10.1016/j.cell.2005.06.007 pmcid: 16096061
Xu, M. et al. A systematic integrated analysis of brain expression profiles reveals YAP1 and other prioritized hub genes as important upstream regulators in Alzheimer’s disease. Alzheimers Dement 14, 215–229 (2018).
pubmed: 28923553 doi: 10.1016/j.jalz.2017.08.012 pmcid: 28923553
Zhao, B., Lei, Q. Y. & Guan, K. L. The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr. Opin. Cell Biol. 20, 638–646 (2008).
pubmed: 18955139 pmcid: 3296452 doi: 10.1016/j.ceb.2008.10.001
Saucedo, L. J. & Edgar, B. A. Filling out the Hippo pathway. Nat. Rev. Mol. Cell Biol. 8, 613–621 (2007).
pubmed: 17622252 doi: 10.1038/nrm2221 pmcid: 17622252
Zhao, B., Li, L., Tumaneng, K., Wang, C. Y. & Guan, K. L. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev. 24, 72–85 (2010).
pubmed: 20048001 pmcid: 2802193 doi: 10.1101/gad.1843810
Basu, S., Totty, N. F., Irwin, M. S., Sudol, M. & Downward, J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol. Cell 11, 11–23 (2003).
pubmed: 12535517 doi: 10.1016/S1097-2765(02)00776-1 pmcid: 12535517
Strano, S. et al. The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage. Mol. Cell 18, 447–459 (2005).
pubmed: 15893728 doi: 10.1016/j.molcel.2005.04.008 pmcid: 15893728
Levy, D., Adamovich, Y., Reuven, N. & Shaul, Y. Yap1 phosphorylation by c-Abl is a critical step in selective activation of proapoptotic genes in response to DNA damage. Mol. Cell 29, 350–361 (2008).
pubmed: 18280240 doi: 10.1016/j.molcel.2007.12.022 pmcid: 18280240
Hoshino, M. et al. Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73. J. Cell Biol. 172, 589–604 (2006).
pubmed: 16461361 pmcid: 2063678 doi: 10.1083/jcb.200509132
Mao, Y. et al. The hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression through impaired RNA splicing. Cell Death Dis. 7, e2207 (2016).
pubmed: 27124581 pmcid: 4855646 doi: 10.1038/cddis.2016.101
Mao, Y. et al. Targeting TEAD/YAP-transcription-dependent necrosis, TRIAD, ameliorates Huntington’s disease pathology. Hum. Mol. Genet. 25, 4749–4770 (2016).
pubmed: 28171658 pmcid: 28171658
Tagawa, K. et al. Comprehensive phosphoproteome analysis unravels the core signaling network that initiates the earliest synapse pathology in preclinical Alzheimer’s disease brain. Hum. Mol. Genet. 24, 540–558 (2015).
pubmed: 25231903 doi: 10.1093/hmg/ddu475 pmcid: 25231903
Calabrese, B. & Halpain, S. Essential role for the PKC target MARCKS in maintaining dendritic spine morphology. Neuron 48, 77–90 (2005).
pubmed: 16202710 doi: 10.1016/j.neuron.2005.08.027 pmcid: 16202710
Fujita, K. et al. HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer’s disease. Sci. Rep. 6, 31895 (2016).
pubmed: 27557632 pmcid: 4997258 doi: 10.1038/srep31895
Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).
pubmed: 12110890 doi: 10.1038/nature00858 pmcid: 12110890
Lotze, M. T. & Tracey, K. J. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat. Rev. Immunol. 5, 331–342 (2005).
pubmed: 15803152 doi: 10.1038/nri1594 pmcid: 15803152
Nakamura, A. et al. High performance plasma amyloid-beta biomarkers for Alzheimer’s disease. Nature 554, 249–254 (2018).
pubmed: 29420472 doi: 10.1038/nature25456 pmcid: 29420472
Arbuzova, A., Schmitz, A. A. & Vergeres, G. Cross-talk unfolded: MARCKS proteins. Biochem J. 362, 1–12 (2002).
pubmed: 11829734 pmcid: 1222354 doi: 10.1042/bj3620001
Zhang, Y. & Bhavnani, B. R. Glutamate-induced apoptosis in neuronal cells is mediated via caspase-dependent and independent mechanisms involving calpain and caspase-3 proteases as well as apoptosis inducing factor (AIF) and this process is inhibited by equine estrogens. BMC Neurosci. 7, 49 (2006).
pubmed: 16776830 pmcid: 1526740 doi: 10.1186/1471-2202-7-49
Du, Y. et al. Activation of a caspase 3-related cysteine protease is required for glutamate-mediated apoptosis of cultured cerebellar granule neurons. Proc. Natl Acad. Sci. USA 94, 11657–11662 (1997).
pubmed: 9326666 doi: 10.1073/pnas.94.21.11657 pmcid: 9326666
Dessi, F., Charriaut-Marlangue, C., Khrestchatisky, M. & Ben-Ari, Y. Glutamate-induced neuronal death is not a programmed cell death in cerebellar culture. J. Neurochem. 60, 1953–1955 (1993).
pubmed: 8097239 doi: 10.1111/j.1471-4159.1993.tb13427.x pmcid: 8097239
Silva, M. T. Secondary necrosis: the natural outcome of the complete apoptotic program. FEBS Lett. 584, 4491–4499 (2010).
pubmed: 20974143 doi: 10.1016/j.febslet.2010.10.046 pmcid: 20974143
Bergsbaken, T., Fink, S. L. & Cookson, B. T. Pyroptosis: host cell death and inflammation. Nat. Rev. Microbiol 7, 99–109 (2009).
pubmed: 19148178 pmcid: 2910423 doi: 10.1038/nrmicro2070
Fink, S. L. & Cookson, B. T. Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol 8, 1812–1825 (2006).
pubmed: 16824040 doi: 10.1111/j.1462-5822.2006.00751.x pmcid: 16824040
Oakley, H. et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140 (2006).
pubmed: 17021169 pmcid: 6674618 doi: 10.1523/JNEUROSCI.1202-06.2006
Saito, T. et al. Single App knock-in mouse models of Alzheimer’s disease. Nat. Neurosci. 17, 661–663 (2014).
pubmed: 24728269 doi: 10.1038/nn.3697 pmcid: 24728269
Meng, Z., Moroishi, T. & Guan, K. L. Mechanisms of Hippo pathway regulation. Genes Dev. 30, 1–17 (2016).
pubmed: 26728553 pmcid: 4701972 doi: 10.1101/gad.274027.115
Caccamo, A. et al. Necroptosis activation in Alzheimer’s disease. Nat. Neurosci. 20, 1236–1246 (2017).
pubmed: 28758999 doi: 10.1038/nn.4608
Tanaka, H. et al. The intellectual disability gene PQBP1 rescues Alzheimer’s disease pathology. Mol. Psychiatry 23, 2090–2110 (2018).
pubmed: 30283027 pmcid: 6250680 doi: 10.1038/s41380-018-0253-8
Kawano, S. et al. A cell-based screening for TAZ activators identifies ethacridine, a widely used antiseptic and abortifacient, as a compound that promotes dephosphorylation of TAZ and inhibits adipogenesis in C3H10T1/2 cells. J. Biochem. 158, 413–423 (2015).
pubmed: 25979969 doi: 10.1093/jb/mvv051
Shoji, M. et al. JNK activation is associated with intracellular beta-amyloid accumulation. Brain Res. Mol. Brain Res. 85, 221–233 (2000).
pubmed: 11146125 doi: 10.1016/S0169-328X(00)00245-X
LaFerla, F. M., Green, K. N. & Oddo, S. Intracellular amyloid-beta in Alzheimer’s disease. Nat. Rev. Neurosci. 8, 499–509 (2007).
pubmed: 17551515 doi: 10.1038/nrn2168 pmcid: 17551515
Cai, Z. et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat. Cell Biol. 16, 55–65 (2014).
pubmed: 24316671 doi: 10.1038/ncb2883 pmcid: 24316671
Galluzzi, L., Kepp, O. & Kroemer, G. MLKL regulates necrotic plasma membrane permeabilization. Cell Res. 24, 139–140 (2014).
pubmed: 24418759 pmcid: 3915909 doi: 10.1038/cr.2014.8
Dondelinger, Y. et al. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep. 7, 971–981 (2014).
pubmed: 24813885 doi: 10.1016/j.celrep.2014.04.026 pmcid: 24813885
Wang, H. et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54, 133–146 (2014).
pubmed: 24703947 doi: 10.1016/j.molcel.2014.03.003 pmcid: 24703947
Yang, Y., Mufson, E. J. & Herrup, K. Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer’s disease. J. Neurosci. 23, 2557–2563 (2003).
pubmed: 12684440 pmcid: 6742098 doi: 10.1523/JNEUROSCI.23-07-02557.2003
Mesrouze, Y. et al. Adaptation of the bound intrinsically disordered protein YAP to mutations at the YAP:TEAD interface. Protein Sci. 27, 1810–1820 (2018).
pubmed: 30058229 pmcid: 6199158 doi: 10.1002/pro.3493
Uversky, V. N. Intrinsically disordered proteins and their (disordered) proteomes in neurodegenerative disorders. Front Aging Neurosci. 7, 18 (2015).
pubmed: 25784874 pmcid: 4345837 doi: 10.3389/fnagi.2015.00018
Hirano, A., Dembitzer, H. M., Kurland, L. T. & Zimmerman, H. M. The fine structure of some intraganglionic alterations. Neurofibrillary tangles, granulovacuolar bodies and “rod-like” structures as seen in Guam amyotrophic lateral sclerosis and parkinsonism-dementia complex. J. Neuropathol. Exp. Neurol. 27, 167–182 (1968).
pubmed: 5646193 doi: 10.1097/00005072-196804000-00001 pmcid: 5646193
Dickson, D. W. et al. Ballooned neurons in select neurodegenerative diseases contain phosphorylated neurofilament epitopes. Acta Neuropathol. 71, 216–223 (1986).
pubmed: 2432750 doi: 10.1007/BF00688042 pmcid: 2432750
Yamanishi, E. et al. A novel form of necrosis, TRIAD, occurs in human Huntington’s disease. Acta Neuropathol. Commun. 5, 19 (2017).
pubmed: 28274274 pmcid: 5341362 doi: 10.1186/s40478-017-0420-1
Rebeiz, J. J., Kolodny, E. H. & Richardson, E. P. Jr. Corticodentatonigral degeneration with neuronal achromasia. Arch. Neurol. 18, 20–33 (1968).
pubmed: 5634369 doi: 10.1001/archneur.1968.00470310034003 pmcid: 5634369
Gibb, W. R., Luthert, P. J. & Marsden, C. D. Corticobasal degeneration. Brain 112, 1171–1192 (1989).
pubmed: 2478251 doi: 10.1093/brain/112.5.1171 pmcid: 2478251
Lippa, C. F., Smith, T. W. & DeGirolami, U. Lobar atrophy with pontine neuronal chromatolysis (“ballooned” neurons). Hum. Pathol. 21, 1076–1079 (1990).
pubmed: 2210731 doi: 10.1016/0046-8177(90)90260-C pmcid: 2210731
Lowe, J. et al. Ballooned neurons in several neurodegenerative diseases and stroke contain alpha B crystallin. Neuropathol. Appl Neurobiol. 18, 341–350 (1992).
pubmed: 1528389 doi: 10.1111/j.1365-2990.1992.tb00796.x pmcid: 1528389
Mori, H. & Oda, M. Ballooned neurons in corticobasal degeneration and progressive supranuclear palsy. Neuropathology 17, 248–252 (1997).
doi: 10.1111/j.1440-1789.1997.tb00047.x
Sakurai, A. et al. Fragmentation of the Golgi apparatus of the ballooned neurons in patients with corticobasal degeneration and Creutzfeldt-Jakob disease. Acta Neuropathol. 100, 270–274 (2000).
pubmed: 10965796 doi: 10.1007/s004010000182 pmcid: 10965796
Yang, G., Pan, F., Parkhurst, C. N., Grutzendler, J. & Gan, W. B. Thinned-skull cranial window technique for long-term imaging of the cortex in live mice. Nat. Protoc. 5, 201–208 (2010).
pubmed: 20134419 pmcid: 4690457 doi: 10.1038/nprot.2009.222
Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).
pubmed: 21654799 pmcid: 21654799 doi: 10.1038/nature10137

Auteurs

Hikari Tanaka (H)

Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

Hidenori Homma (H)

Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

Kyota Fujita (K)

Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

Kanoh Kondo (K)

Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

Shingo Yamada (S)

Shino-Test Corporation, 2-29-14, Ohino-dai, Minami-ku, Sagamihara, Kanagawa, 252-0331, Japan.

Xiaocen Jin (X)

Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

Masaaki Waragai (M)

Department of Neurology, Higashi Matsudo Municipal Hospital, Matsudo, Chiba, 270-2222, Japan.
ORCID: 0000-0003-4874-6154

Gaku Ohtomo (G)

Department of Neurology, The University of Tokyo, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Atsushi Iwata (A)

Department of Neurology, The University of Tokyo, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Kazuhiko Tagawa (K)

Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

Naoki Atsuta (N)

Department of Neurology, Brain and Mind Research Center, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.

Masahisa Katsuno (M)

Department of Neurology, Brain and Mind Research Center, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
ORCID: 0000-0001-9453-9311

Naoki Tomita (N)

Department of Geriatrics & Gerontology, Division of Brain Science, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-cho, Aoba-ku, Sendai, 980-8575, Japan.

Katsutoshi Furukawa (K)

Department of Geriatrics & Gerontology, Division of Brain Science, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-cho, Aoba-ku, Sendai, 980-8575, Japan.

Yuko Saito (Y)

Department of Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higahsi-machi, Kodaira, Tokyo, Japan.

Takashi Saito (T)

Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.

Ayaka Ichise (A)

Department of Physiology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Shinsuke Shibata (S)

Department of Physiology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
ORCID: 0000-0002-1185-9043

Hiroyuki Arai (H)

Department of Geriatrics & Gerontology, Division of Brain Science, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-cho, Aoba-ku, Sendai, 980-8575, Japan.

Takaomi Saido (T)

Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.

Marius Sudol (M)

Department of Physiology, National University of Singapore, Yong Loo Li School of Medicine, 2 Medical Drive, Singapore, 117597, Singapore.

Shin-Ichi Muramatsu (SI)

Department of Neurology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0496, Japan.
ORCID: 0000-0002-3185-7790

Hideyuki Okano (H)

Department of Physiology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Elliott J Mufson (EJ)

Department of Neurobiology and Neurology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ, 85013, USA.

Gen Sobue (G)

Department of Neurology, Brain and Mind Research Center, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
ORCID: 0000-0003-4769-5922

Shigeo Murayama (S)

Department of Neuropathology, Brain Bank for Aging Research, Tokyo Metropolitan Institute of Gerontology, 35-2, Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.

Hitoshi Okazawa (H)

Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. okazawa.npat@mri.tmd.ac.jp.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Peptides bêta-amyloïdes › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Eucaryotes › Animaux › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du cycle cellulaire › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Noyau de la cellule › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Troubles de la cognition › Dysfonctionnement cognitif › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Réticulum endoplasmique › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines chromosomiques nonhistones › Protéines HMG › Protéines HMGB › Protéine HMGB1 › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches pluripotentes induites › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Lipides › Lipides membranaires › Phospholipides › Glycérophosphate › Acides phosphatidiques › Lysophospholipides › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Nécrose › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Cellules › Neurones › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Composés chimiques organiques › Amines › Aminoalcools › Sphingosine › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Sciences de l'information › Processus de copie › Enregistrement sur magnétoscope › Imagerie accélérée › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › YAP-dependent necrosis occurs in early stages...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Protéines de signalisation YAP › YAP-dependent necrosis occurs in early stages...