Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-08-10
1999-08-10
Duffy, Patricia A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 23, 514 79, 514 91, 514 95, 514359, 514438, 514439, 514443, 514569, 514642, 514647, 548100, 548121, 548122, 530300, 530322, 536 111, A61K 3800, A61K 31135, A61K 3170
Patent
active
059359277
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates generally to the non-enzymatic glycosylation of amyloid proteins and the often consequent formation of advanced glycosylation endproducts (AGEs). Formation of AGE-amyloid can result in disease conditions or complications. The invention particularly relates to compositions and methods for the prevention and treatment of amyloidosis associated with neurodegenerative diseases, in particular Alzheimer's disease, and amyloidosis associated with Type II (adult onset) diabetes.
BACKGROUND OF THE INVENTION
Amyloidosis and the .beta.-Amyloid Peptide
Amyloidosis generally refers to a physiological condition which involves deposition of insoluble polypeptides, termed amyloid polypeptides or amyloid proteins. There are a wide range of amyloid proteins found in various tissues throughout a subject, and a number of pathological conditions associated with various amyloidoses. For example, multiple myeloma can result in amyloidosis with the immunoglobulin proteins. Idiopathic familial Mediterranean fever also involves systemic amyloidosis. Perhaps the best known disease associated with amyloidosis is Alzheimer's disease.
Alzheimer's disease (AD) affects more than 30% of humans over 80 years of age, and as such, represents one of the most important health problems of developed countries (Evans et al., 1989, JAMA 262:2551-56; Katzman and Saitoh, 1991, FASEB J. 280:278-286). The etiology and pathogenesis of this progressive dementia is poorly understood, but symptomatic disease is associated with deposits of amyloid plaques, cerebrovascular amyloid and neurofibrillary tangles in the brain and cerebrovasculature. The number of plaques in AD patients' brains are typically 5- to-10 fold greater than in age-matched healthy controls. Increased levels of plaques may result from increased rate of synthesis of the components of the plaques, decreased rate of degradation, or some combination of the two.
The primary protein component of plaques is the 42 amino acid (4.2 kDa) beta-Amyloid Peptide (.beta.AP), which derives from a family of larger Amyloid Peptide Precursor (APP) proteins (Glenner and Wong, 1984, Biochem. Biophys. Res. Commun. 120:885-890; Glenner and Wong, 1984, Biochem. Biophys. Res. Commun. 122:1131-35; Goidgaber et al., 1987, Science 235:8778-8780; Kang et al., 1987, Nature 325:733-736; Robakis et al., 1987, Proc. Natl. Acad. Sci. USA 84:4190-4194; Tanzi et al., 1987, Science 235:880-884). The process of amyloidosis is poorly understood, but requires at least .beta.AP. Recent evidence shows that .beta.AP may be found in extracellular spaces like cerebrospinal fluid (CSF) of the brain and conditioned media of many cell types. Since increased amounts of amyloid deposits are present in AD brains one simple hypothesis is that increased .beta.AP production leads to increased amyloidosis. Messenger RNAs encoding the APP precursors of .beta.AP increase about 2-fold in AD brains, which has suggested to some a possible 2-fold increase in rates of translation, which may explain increased amyloid plaque formation (e.g., Jacobsen et al., 1991, Neurobiol. Aging 12:585-592, and references cited therein; Palmert et al., 1989, Prog. Clin. Biol. Res. 317:971-984; Tanaka et al., 1990, Rinsho Byori 38:489-493; Tanaka et al., 1989, Biochem. Biophys. Res. Commun. 165:1406-1414). An example of an increased efficiency of .beta.AP production that correlates with increased plaque levels is found in a rare genetically linked familial form of Alzheimer's disease (Cai et al., 1992, Science 259:514-516; Citron et al., 1992, Nature 360:672-674; Mullan et al., 1992, Nature Genet. 1:345-347), known as a Swedish disease involving a double lysine-methionine (KM) to asparagine-leucine (NL) mutation in APP near the amino-terninus of .beta.AP. This mutation increases the release of extracellular .beta.AP in cultured cells. However, while this observation may partly explain amyloidosis in the Swedish disease (and Down's Syndrome), .beta.AP peptide levels in CSF of AD and healthy patients are the
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Bucala Richard J.
Cerami Anthony
Ulrich Peter C.
Vitek Michael P.
Vlassara Helen
Duffy Patricia A.
The Picower Institute for Medical Research
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