Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1997-08-04
1999-10-26
Duffy, Patricia A.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435 71, 435 79, 435 792, 435 795, 435975, 436525, 436164, 436172, G01N 3353
Patent
active
059726342
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The purpose of this invention is to assay the quantity and quality of A.beta. peptide in Alzheimer's disease (AD) and A.beta. amyloidotic disorders related to Alzheimer's disease. Specifically, the invention proposes to achieve this end by enriching the peptide by capturing it from biological fluids such as plasma, serum, cerebrospinal fluid or urine with a zinc- or copper-chelated microwell plate, and then measuring the amounts of captured A.beta. with specific anti-A.beta. antibodies in an ELISA.
2. Related Art
Alzheimer's disease is characterized pathologically by the accumulation in the brain of A.beta. protein. The A.beta. protein is a small peptide that is also found in cerebrospinal fluid and plasma. Much evidence implicates the accumulation of A.beta. in the pathogenesis of the disease, either as the neurotoxic agent itself or as a hallmark which accompanies neurotoxicity in the disorder. A.beta. accumulates as a highly insoluble deposit within neuronal tissues. It is desirable to discover a treatment which would reverse the deposition and relieve or arrest clinical deterioration.
Aggregation of A.beta. in the brain is believed to contribute to the progressive dementia, characteristic of Alzheimer's disease (AD) and to the premature AD observed among Down's syndrome patients. A.beta., a 4.3-kDa peptide, is the principal constituent of the cerebral amyloid deposits, a pathological hallmark of Alzheimer's disease (AD) (Masters et al., Proc. Natl. Acad. Sci. USA 82:4245-4249 (1985); Glenner & Wong, Biochem. Biophys. Rev. Commun. 120:885-890 (1984)). A.beta. is derived from the much larger amyloid protein precursor (APP) (Kang et al., Nature 325:733-736 (1987); Tanzi et al., Science 235:880-884 (1987); Robakis et al., Proc. Natl. Acad. Sci. USA 84:4190-4194 (1987); Goldgaber et al., Science 235:877-880 (1987)), whose physiological function remains unclear. The cause of Alzheimer's disease remains elusive; however, the discovery of mutations of APP close to or within the A.beta. domain (Goate et al., Nature 349:704-706 (1991); Levy et al., Science 248:1124-1126 (1990); Murrell et al., Science 254:97-99 (1991); Hendricks et al., Nature Genet. 1:218-221 (1992), linked to familial AD (FAD) (E. Levy et al., Science 248:1124 (1990); A.beta. Goate et al., Nature 349:704 (1991); M. Chartier-Harlin et al., Nature 353:844 (1991); J. Murrell, M. Farlow, B. Ghetti, M. D. Benson, Science 254:97 (1991); L. Hendricks et al., Nature Genet. 1:218 (1992); M. Mullan et al., Nature Genet. 1:345 (1992)), indicates that the metabolism of A.beta. and APP is likely to be intimately involved with the pathophysiology of this disorder.
Alzheimer's disease affects 10% of individuals over the age of 60, however, the existence of A.beta. deposits in 40% of the brains of normal individuals in their forties suggests an even larger subclinical prevalence. Hence, the disease process is likely to be very common, with individual thresholds of neuronal and functional reserve being responsible for the varying onset of clinical symptoms. The disease is debilitating, chronic, incurable and very expensive to treat and an effective prevention or therapy would have an enormous commercial market. However, there are no reliable biochemical markers for AD.
FAD patients with the "Swedish" APP mutation overproduce the soluble, secreted form of A.beta. and suffer from early onset (<60 years) AD (Citron et al., Nature 360:672-674 (1992)). A potential neuropathogenic mechanism has been reported by Younkin and colleagues (Society for Neuroscience, Mol. Genet. Med. 3:95-137 (1993)) for the APP 717 mutations which account for 90% of the APP mutations causing FAD. These mutations apparently lead to an increase in the ratio of "long" A.beta. (1-42) to Ad (1-40). A.beta. (1-40) is the predominant species in the cerebrospinal fluid (CSF), and is a relatively soluble peptide. A.beta. (1-42) is significantly more amyloidogenic, and its overproduction relative to the 1-40 species appears to lead to early-
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Bush Ashley I.
Moir Robert D.
Tanzi Rudolph E.
Duffy Patricia A.
The General Hospital Corporation
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