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WO2000067016A1 - Procedes d'identification de composes pour le traitement de la maladie d'alzheimer - Google Patents

Procedes d'identification de composes pour le traitement de la maladie d'alzheimer Download PDF

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Publication number
WO2000067016A1
WO2000067016A1 PCT/US2000/011401 US0011401W WO0067016A1 WO 2000067016 A1 WO2000067016 A1 WO 2000067016A1 US 0011401 W US0011401 W US 0011401W WO 0067016 A1 WO0067016 A1 WO 0067016A1
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WO
WIPO (PCT)
Prior art keywords
cell
compound
candidate compound
activity
mouse
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2000/011401
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English (en)
Other versions
WO2000067016A9 (fr
Inventor
Ralph A. Nixon
Anne M. Cataldo
Paul M. Mathews
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NATHAN S KLINE INSTITUTE FOR PSYCHIATRIC RESEARCH
Original Assignee
NATHAN S KLINE INSTITUTE FOR PSYCHIATRIC RESEARCH
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Filing date
Publication date
Application filed by NATHAN S KLINE INSTITUTE FOR PSYCHIATRIC RESEARCH filed Critical NATHAN S KLINE INSTITUTE FOR PSYCHIATRIC RESEARCH
Priority to JP2000615804A priority Critical patent/JP2002543425A/ja
Priority to AU46734/00A priority patent/AU772054B2/en
Priority to EP00928500A priority patent/EP1181550A4/fr
Priority to CA002370177A priority patent/CA2370177A1/fr
Publication of WO2000067016A1 publication Critical patent/WO2000067016A1/fr
Anticipated expiration legal-status Critical
Publication of WO2000067016A9 publication Critical patent/WO2000067016A9/fr
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A01K67/0278—Knock-in vertebrates, e.g. humanised vertebrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6478—Aspartic endopeptidases (3.4.23)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2207/00—Modified animals
    • A01K2207/15—Humanized animals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0306—Animal model for genetic diseases
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0306—Animal model for genetic diseases
    • A01K2267/0312—Animal model for Alzheimer's disease
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0306—Animal model for genetic diseases
    • A01K2267/0318—Animal model for neurodegenerative disease, e.g. non- Alzheimer's
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/916—Hydrolases (3) acting on ester bonds (3.1), e.g. phosphatases (3.1.3), phospholipases C or phospholipases D (3.1.4)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • Thy-1.1 promoter which has been used successfully in mice transgenic for mutant APP that show amyloid plaque deposition (Sturchler-Pierrat et al, Proc. Natl. Acad. Sci. USA 94: 13287-13292, 1997).
  • the Thy-1.1 promoter is valuable in that high levels of transgene expression have been obtained and that expression is restricted within the CNS to neurons.
  • An 8.2 kb EcoRI mouse genomic fragment containing the whole Thy-1.1 gene forms the core of the transgene constructs (Chang et al, Proc. Natl. Acad. Sci.
  • Ts65Dn mice but not TslCje mice, show abnormally large endosomes, this indicates that genes in this part of the chromosome (the App to Sodl region) are essential to the development of this defect.
  • the TslCje mice do not show BFCN degeneration, this result would suggest that endosomal system upregulation and BFCN degeneration share a common genetic underpinning in these animals. While the App gene in this region is likely to be of importance, we suspect that a dosage-effect for APP will not fully explain the Ts65Dn endosomal system upregulation, as we have not seen abnormally large endosomes in the APPswe transgenic mice nor do APP overexpressing mice develop BFCN degeneration. Characterizing the MslTs65 mice that carry an extra copy of App but lack many of the other genes over represented in Ts65Dn mice will directly complement our analysis of the other mice.
  • the supernatant was collected, neutralized with 0.1 volume 0.5 M Tris, pH 6.8, and loaded in duplicate wells both neat and diluted 1:2 in EC buffer (20mM Na phosphate, 2 mM EDTA, 400mM NaCl, 0.2 BSA, 0.4% Block Ace, 0.95% CHAPS).
  • the DEA extraction protocol has been shown to efficiently recover immunoreactive A ⁇ from mouse brain homogenates and leave both full-length and sAPP in the 100,000 x g pellet (Savage et al., J. Neurosci. 18:1743-1752, 1998).
  • conditioned media collected from cells was loaded neat and 1 :2.
  • a ⁇ -40 and A ⁇ -42 peptide standards were purchased from American Peptide Co.
  • APP and APP metabolites are immunoprecipitated using any of a number of antibodies known to those skilled in the art, followed by separation using SDS-PAGE. Gels are exposed to X-ray film or are analyzed quantitatively using a Phosphoimager. Immunocytochemistry and digital confocal microscopic analysis

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Genetics & Genomics (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Environmental Sciences (AREA)
  • Microbiology (AREA)
  • Veterinary Medicine (AREA)
  • General Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Biophysics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Animal Husbandry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Toxicology (AREA)
  • Physics & Mathematics (AREA)
  • Biodiversity & Conservation Biology (AREA)
  • Cell Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Analytical Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Plant Pathology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)

Abstract

Cette invention se rapporte à des procédés permettant d'identifier des composés utiles au traitement de la maladie d'Alzheimer.
PCT/US2000/011401 1999-04-30 2000-04-28 Procedes d'identification de composes pour le traitement de la maladie d'alzheimer Ceased WO2000067016A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2000615804A JP2002543425A (ja) 1999-04-30 2000-04-28 アルツハイマー病の治療のための化合物の同定法
AU46734/00A AU772054B2 (en) 1999-04-30 2000-04-28 Methods for the identification of compounds for the treatment of alzheimer's disease
EP00928500A EP1181550A4 (fr) 1999-04-30 2000-04-28 Procedes d'identification de composes pour le traitement de la maladie d'alzheimer
CA002370177A CA2370177A1 (fr) 1999-04-30 2000-04-28 Procedes d'identification de composes pour le traitement de la maladie d'alzheimer

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US13199199P 1999-04-30 1999-04-30
US13189099P 1999-04-30 1999-04-30
US60/131,991 1999-04-30
US60/131,890 1999-04-30
US14064499P 1999-06-23 1999-06-23
US14064399P 1999-06-23 1999-06-23
US60/140,643 1999-06-23
US60/140,644 1999-06-23

Publications (2)

Publication Number Publication Date
WO2000067016A1 true WO2000067016A1 (fr) 2000-11-09
WO2000067016A9 WO2000067016A9 (fr) 2002-07-11

Family

ID=27494932

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2000/011739 Ceased WO2000066617A1 (fr) 1999-04-30 2000-04-28 Methodes de traitement de demence neuronale associee a une atrophie
PCT/US2000/011401 Ceased WO2000067016A1 (fr) 1999-04-30 2000-04-28 Procedes d'identification de composes pour le traitement de la maladie d'alzheimer

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/US2000/011739 Ceased WO2000066617A1 (fr) 1999-04-30 2000-04-28 Methodes de traitement de demence neuronale associee a une atrophie

Country Status (5)

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EP (2) EP1181550A4 (fr)
JP (2) JP2003514216A (fr)
AU (2) AU784048B2 (fr)
CA (2) CA2370177A1 (fr)
WO (2) WO2000066617A1 (fr)

Families Citing this family (9)

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ES2314056T3 (es) * 2001-05-02 2009-03-16 Blanchette Rockefeller Neurosciences Institute Activadores de la anhidrasa carbonica para mejorar el aprendizaje y la memoria.
WO2004089369A2 (fr) * 2003-04-11 2004-10-21 Cambridge University Technical Services Limited Methodes et moyens permettant de traiter des troubles de conformation des proteines
TW201207390A (en) 2004-05-18 2012-02-16 Brni Neurosciences Inst Method for screening agent for antidepressant activity
ES2301280A1 (es) * 2005-05-16 2008-06-16 Fina Biotech S.L.U. Metodo para diagnosticar la enfermedad de alzheimer.
US10278774B2 (en) 2011-03-18 2019-05-07 Covidien Lp Selectively expandable operative element support structure and methods of use
JP6391318B2 (ja) * 2014-06-27 2018-09-19 学校法人順天堂 アルツハイマー病予防治療薬のスクリーニング法
JP7344546B2 (ja) * 2019-08-28 2023-09-14 日本メナード化粧品株式会社 Ａｐｅｈ産生促進剤
CN111686129A (zh) * 2020-04-14 2020-09-22 南开大学 一种溶酶体作为制备治疗阿尔兹海默症及延缓老年智力衰退药物领域的应用
CN114209716B (zh) * 2021-11-26 2024-06-25 南开大学 一种改性溶酶体作为制备治疗蛋白错误折叠或加工类疾病药物的应用

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US6294520B1 (en) * 1989-03-27 2001-09-25 Albert T. Naito Material for passage through the blood-brain barrier
US5538983A (en) * 1990-05-16 1996-07-23 The Rockefeller University Method of treating amyloidosis by modulation of calcium
WO1994007144A1 (fr) * 1992-09-21 1994-03-31 United States Of America, As Represented By The Secretary, Department Of Health And Human Services Procede de criblage de composes et procedes pour traiter la maladie d'alzheimer
US5686269A (en) * 1994-07-28 1997-11-11 The Mclean Hospital Corporation Method of diagnosing Alzheimer's disease by detecting the level of cathepsin D in cerebrospinal fluid
AUPN991796A0 (en) * 1996-05-17 1996-06-13 Women's And Children's Hospital Early detection of lysosomal storage disorders
WO1998021589A1 (fr) * 1996-11-15 1998-05-22 The Trustees Of The University Of Pennsylvania Recherche de modulateurs de la transformation de l'amyloide
US6268479B1 (en) * 1997-03-12 2001-07-31 The Trustees Of Columbia University In The City Of New York Intracellular amyloid-beta peptide binding (ERAB) polypeptide

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Title
CATALDO ET. AL.: "Increased Neuronal Endocytosis and Protease Delivery to Early Endosomes in Sporadic Alzheimer's Disease: Neuropathologic Evidence for a Mechanism of Increased beta Amyloidogenesis", JOURNAL OF NEUROSCIENCE, vol. 17, no. 16, 15 August 1997 (1997-08-15), pages 6142 - 6151, XP002929849 *
CATALDO ET. AL.: "Lysosomal Hydrolases of Different Classes are Abnormally Distributed in Brains pf Patients with Alzheimer Disease", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCE (USA), vol. 88, December 1991 (1991-12-01), pages 10998 - 11002, XP002929850 *
DASH ET. AL.: "Inhibitors of Endocytosis, Endosome Fusion and Lysosomal Processing Inhibit the Intracellular Proteolysis of the Amyloid Precursor Protein", NEUROSCIENCE LETTERS, vol. 164, 1993, pages 183 - 186, XP002929851 *
GRANHOLM ET. AL.: "Segmental Trisomy Ts65Dn Mice Have a Decrease in Nervev Growth Factor Receptors in Septal Forebrain Neurons", SOCIETY FOR NEUROSCIENCE, vol. 24, no. 2, 1998, pages 2008, XP002929846 *
HAASS ET. AL.: "Targeting of Cell-Surface beta-Amyloid Precursor Protein to Lysosomes: Alternative Processing into Amyloid Bearing Fragments", NATURE, vol. 357, 11 June 1992 (1992-06-11), pages 500 - 503, XP000573989 *
HOLTZMAN ET. AL.: "Development Abnormalities and Age-Related Neurodegeneration in a Mouse Model of Down Syndrome", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCE (USA), vol. 93, November 1996 (1996-11-01), pages 13333 - 13338, XP002929848 *
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See also references of EP1181550A4 *

Also Published As

Publication number Publication date
WO2000067016A9 (fr) 2002-07-11
JP2002543425A (ja) 2002-12-17
AU772054B2 (en) 2004-04-08
EP1181550A4 (fr) 2005-03-02
EP1181308A1 (fr) 2002-02-27
CA2370177A1 (fr) 2000-11-09
WO2000066617A1 (fr) 2000-11-09
CA2372190A1 (fr) 2000-11-09
AU784048B2 (en) 2006-01-19
AU4686300A (en) 2000-11-17
EP1181308A4 (fr) 2004-10-27
EP1181550A1 (fr) 2002-02-27
AU4673400A (en) 2000-11-17
JP2003514216A (ja) 2003-04-15

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