Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-09-04
2002-01-29
Arthur, Lisa B. (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200
Reexamination Certificate
active
06342350
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the area of medical genetics. Specifically, the invention provides a genetic test to identify carriers of specific alleles of the Alpha-2-Macroglobulin gene, the occurrence of which are genetically linked, with high statistical significance, to the condition known as Alzheimer's disease.
2. Related Art
Alpha-2-Macroglobulin (&agr;
2
M) is a major serum pan-protease inhibitor which inhibits all four classes of proteases by a unique steric trapping mechanism (Borth, W.,
FASEB
6:3345-3353 (1992)). It is the major representative of a family of plasma proteins, most of which possess a unique internal, cyclic thiol ester bond, referred to as the &agr;-macroglobulins (Borth, W.,
FASEB
6:3345-3353 (1992)). Although it functions against a wide variety of human and bacterial endopeptidases (Starkey, P. M. and Barret, A. J.,
Proteinases in mammalian cells and tissues
, Barret, A. J. (ed.), North-Holland, N.Y. (pub), pp. 663-696, (1977)), a possible role in pathogenesis is not yet known. In vitro studies have provided a great deal of information regarding protein structure and inhibitory functions (Scottrup-Jensen, L., et al.,
J Biol. Chem.
259:8318-8327 (1984); Feldman, S. R., et al.,
Proc. Natl. Acad. Sci. USA
82:5700-5704, 1985; Kan, C. C., et al.,
Proc. Natl. Acad Sci USA
82:2282-2286 (1985); Bretaudiere, J. P., et al.,
Proc. Natl. Acad. Sci. USA
85:1437-1441 (1988); Van leuven, F., et al.,
J Biol. Chem.
261:11369-11373 (1986)), and at the molecular level, it is known to be part of a related gene cluster on human chromosome 12p (Devriendt, K., et al.,
Gene
81:325-334, 1989) that also includes the &agr;
2
M pseudogene and the pregnancy-zone gene. Recent evidence suggests that &agr;
2
M may be associated with certain morphological characteristics of Alzheimer's Disease (AD).
AD is a neurodegenerative disorder characterized by a global decline in mental function, memory and acquired intellectual skills. It is the most common form of dementia occurring in mid-to late-life and is a major cause of disability and death in the elderly (Price, L. and Sisodia, S.,
Annu. Rev. Neurosci.
21:479-505 (1998)). The appearance of AD in the population according to age is variable, often being categorized into early and late onset forms. In the general population, 40% of the brains of normal individuals show some evidence of A&bgr; deposits, indicating a subclinical prevalence, and in the population 60 years and older, AD is diagnosed in 10% of the population.
AD is a genetically heterogenous disorder. Early-onset familial AD (EO-FAD) is inherited as an autosomal dominant disorder involving defects in at least three genes, presenilin I (PSENI) on chromosome 14 (Sherrington, R., et al.,
Nature
375:754-760 (1995)), presenilin 2 (PSEN2) on chromosome 1 (Levy-Lehad, E., et al.,
Science
269:973-977 (1995); Rogaev, E. I., et al.,
Nature
376:775-778 (1995)), and &bgr;-amyloid precursor protein (APP) on chromosome 21 (Tanzi, R. E., et al.,
Science
235:880-884 (1987); Goate, A. M., et al.,
Nature
349:704-706 (1991)). These genes account for roughly 30-40% of EO-FAD (Hardy J.,
Trends Neurosci.
20:154-159 (1997); Cruts, M., et al., Hum. Mol.
Genet.
7.43-51 (1998); Blacker, D. and Tanzi, R. E.,
Arch Neurol
55:294-296 (1998)).
Late-onset AD (LOAD) has been associated with the APOE-&egr;4 allele of apolipoprotein E (APOE) located on chromosome 19 (Strittmatter, W. J., et al.,
Proc. Natl. Acad Sci
. (USA) 90:1977-1981 (1993); Saunders, A. M., et al.,
Neurology
43:1467-1472 (1993)). Inheritance of APOE-&egr;4 lowers the age of onset of AD in a dose-dependent manner and is associated with cases of AD occurring from 40 to 90 years. However it has the greatest impact as a risk factor for onset in the 60's (Blacker, D., et al,
Neurology
48:139-147 (1997); Farrer, L. A., et al.,
JAMA
278:1349-1356 (1997)). More recently, the gene encoding the major neuronal receptor for apoE, the low density lipoprotein receptor-related protein (LRP), located on the long arm of chromosome 12, was shown to be associated with LOAD (Kang, D. E., et al.,
Neurology
49:56-61 (1997)).
Neuropathological hallmarks of AD include abundant neurofibrillary tangles (NFIT), and &bgr;-amyloid deposition in cerebral blood vessels and in senile plaques (SP). Deposited amyloid is composed principally of the 40-42 residue &bgr;-amyloid protein (A&bgr;) (Glenner et al.,
Biochem, Biophys Res. Commun.
120:885-890 (1984)), which is a proteolytic fragment of the &bgr;-amyloid precursor protein (APP) Wang et al.,
Nature
325:733-736 (1987)). Pathogenesis is thought to develop in AD patients when the A&bgr; protein is organized into neurotoxic fibrils. In vitro studies demonstrate that A&bgr; is generated as a soluble peptide during cellular metabolism (Haas, C., et al.,
Nature
359:322-325, 1992; Shoji, M., et al.,
Science
258:126-129 (1992)). Several additional plaque-associated proteins are known to promote the in vitro formation of A&bgr; fibrils, suggesting the possibility that these proteins regulate A&bgr; aggregation in vivo (Ma, J., et al.,
Nature
372:92-94 (1994); Eriksson, S., et al.,
Proc Natl. Acad. Sci. USA
92:2313-2317 (1995)). Because A&bgr; deposition likely plays a role in the development of AD, a great deal of research is focused on the synthesis, degradation and clearance of this protein from the affected tissues.
Furthermore, given the potential importance of the APP and A&bgr; proteins in AD pathogenesis, research is also focused on providing a genetic link between mutations in the APP gene and the occurrence of Alzheimer's disease. Mutations in APP close to or in the A&bgr; domain are known (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); Chartier-Harlin, M. et al.,
Nature
353:844 (1991); Mullan, M., et al.,
Nature Genet.
1:345 (1992)). In some instances, linkage of the mutation with the occurrence of familial Alzheimer's disease (FAD) was possible.
Also implicated in the development of AD is the possibility that there exists an imbalance between proteases and protease inhibitors which affects normal amyloid metabolism. Antibodies to ubiquitin strongly react with the characteristic amyloid neurofibrillar tangles (Tabaton, M., et al.,
Proc. Natl. Acad Sci.
88:2098-2102 (1991)). The A&bgr; peptide is generated proteolytically from APP, and proteases cathepsin B and D and protease inhibitors such as protease nexin 1 and &agr;1 -antichymotrypsin were found in amyloid plaques (Cataldo, A. M. and Nixon, R. A.,
Proc. Natl. Acad Sci.
87:3861-3865, 1991; Rosenblatt, D. E., et al.,
Ann. Neurol
26:628-634 (1989); Abraham, C. R., et al.,
Cell
52:487-501 (1988)).
Alpha-2-macroglobulin is another protease inhibitor implicated in neural tissue metabolism. Several lines of evidence link the &agr;
2
M protein to morphological properties associated with AD patient cerebra. One study in support of a role in neural metabolism identified &agr;
2
M as an astroglia-derived neurite-promoting factor for cultured neurons from the rat central nervous system (Mori, T., et al.,
Brain Res.
527:55-61 (1990)). In addition, &agr;
2
M has been shown to attenuate the fibrillogenesis and neurotoxicity of A&bgr; (Hughes, S. R., et al.,
Proc. Natl. Acad. Sci.
(USA) 95:3275-3280 (1998); Du, Y., et al.,
J Neurochem.
70:1182-1188 (1998); Zhang, Z., et al.,
Amyloid: Int. J Exp. Clin. Invest.
3:156-161 (1996)). Also suggestive of a connection between &agr;
2
M and AD is that &agr;
2
M tightly binds the A&bgr; peptide (Du, Y., et al,
J Neurochem.
69:299-305 (1997); Hughes, S. R., et al.,
Proc. Natl. Acad Sci
. (USA) 95:3275-3280 (1998)), and has been shown to mediate the clearance of A&bgr; via endocytosis through LRP (Narita, M., et al.,
J Neurochem.
69: 1904-1911 (1997)). Furthermore, two independent studies found that an &agr;
2
M/protease complex is capable of degrading
Blacker Deborah L.
Hyman Bradley T.
Rebeck George W.
Tanzi Rudolph E.
Arthur Lisa B.
The General Hospital Corporation
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