Title:
METHOD FOR SCREENING FOR ANTI-AMYLOIDOGENIC PROPERTIES AND METHOD FOR TREATMENT OF NEURODEGENERATIVE DISEASE
Document Type and Number:
WIPO Patent Application WO2001060794
Kind Code:
A3
Abstract:
The methodologies of the present invention demonstrate that a critical balance between pro- and anti-amyloidogenic molecules exists that regulates amyloid formation and cell death in Alzheimer's disease and Parkinson's disease. beta -Synuclein, the non-amyloidogenic homologue of alpha -synuclein, is a negative modulator of alpha -synuclein and A beta aggregation, having neuroprotective properties against alpha -synuclein and A beta neurotoxicity and that beta -synuclein and therapeutic agents derived therefrom block amyloidogenesis and neurodegeneration in vivo. The method of the present invention establishes that beta -synuclein blocks A beta aggregation either by direct inhibition of A beta amyloidogenesis or indirectly via either alpha -synuclein or its 35 a.a. NAC region, inferring neuroprotective characteristics within the effected cells. The generation of a transgenic mouse line and a cell-free system overexpressing alpha -synuclein characterizes the mechanisms by which beta -synuclein blocks alpha -synuclein and A beta aggregation and that this mechanism offers protection to the cell against amyloid formation as seen in the pathologies of Alzheimer's disease and Parkinson's disease.
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Inventors:
MASLIAH ELIEZER (US)
Application Number:
PCT/US2001/005569
Publication Date:
January 24, 2002
Filing Date:
February 20, 2001
Export Citation:
Assignee:
UNIV CALIFORNIA (US)
MASLIAH ELIEZER (US)
MASLIAH ELIEZER (US)
International Classes:
A01K67/027; C07K14/47; C12N15/85; A61K38/00; A61K48/00; (IPC1-7): G01N33/00; A01K67/00; C12Q1/02
Other References:
GOLDBERG M.S. ET AL.: "Studies of human alpha-synuclein in transgenic mice", SOCIETY FOR NEUROSCIENCE ABSTRACTS, vol. 25, no. 1-2, 1999, pages 2055, ABSTRACT NO. 819.1, XP002943679
MUCKE L. ET AL.: "Potential roles of alpha1-antichymotrypsin and alpha-synuclein in Alzheimer's pathogenesis assessed in biogenic mice expressing human amyloid precursor proteins", SOCIETY FOR NEUROSCIENCE ABSTRACTS, vol. 25, no. 1-2, 1999, pages 302, ABSTRACT NO. 122.10, XP002943680
COLE G.M. ET AL.: "Amyloid-associated alpha-synuclein (NACP) pathology in aged amyloid precursor transgenic mice", SOCIETY FOR NEUROSCIENCE ABSTRACTS, vol. 25, no. 1-2, 1999, pages 298, ABSTRACT NO. 120.13, XP002943677
HASHIMOTO M. ET AL.: "Human recombinant NACP/alpha-synuclin is aggregated and fibrillated in vitro: Relevance for Lewy body disease", BRAIN RESEARCH, vol. 799, no. 2, 1998, pages 301 - 306, XP002943678
TAKEDA A. ET AL.: "Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders", AMERICAN JOURNAL OF PATHOLOGY, vol. 152, no. 2, February 1998 (1998-02-01), pages 367 - 372, XP002943676
JENSEN P.H. ET AL.: "Binding of A/beta to alpha- and beta-synucleins: identification of segments in alpha-synuclein/NAC precursor that bind Abeta and NAC", BIOCHEMISTRY JOURNAL, vol. 323, 1997, pages 539 - 546, XP002943675
MUCKE L. ET AL.: "Potential roles of alpha1-antichymotrypsin and alpha-synuclein in Alzheimer's pathogenesis assessed in biogenic mice expressing human amyloid precursor proteins", SOCIETY FOR NEUROSCIENCE ABSTRACTS, vol. 25, no. 1-2, 1999, pages 302, ABSTRACT NO. 122.10, XP002943680
COLE G.M. ET AL.: "Amyloid-associated alpha-synuclein (NACP) pathology in aged amyloid precursor transgenic mice", SOCIETY FOR NEUROSCIENCE ABSTRACTS, vol. 25, no. 1-2, 1999, pages 298, ABSTRACT NO. 120.13, XP002943677
HASHIMOTO M. ET AL.: "Human recombinant NACP/alpha-synuclin is aggregated and fibrillated in vitro: Relevance for Lewy body disease", BRAIN RESEARCH, vol. 799, no. 2, 1998, pages 301 - 306, XP002943678
TAKEDA A. ET AL.: "Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders", AMERICAN JOURNAL OF PATHOLOGY, vol. 152, no. 2, February 1998 (1998-02-01), pages 367 - 372, XP002943676
JENSEN P.H. ET AL.: "Binding of A/beta to alpha- and beta-synucleins: identification of segments in alpha-synuclein/NAC precursor that bind Abeta and NAC", BIOCHEMISTRY JOURNAL, vol. 323, 1997, pages 539 - 546, XP002943675
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