Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving hydrolase
Reexamination Certificate
2001-06-20
2004-03-30
Gitomer, Ralph (Department: 1654)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving hydrolase
C435S024000, C435S069200
Reexamination Certificate
active
06713276
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns methods and means for the identification and use of modulators of &bgr;-amyloid (A&bgr;) levels obtained by the proteolytic processing of the &bgr;-amyloid precursor protein, APP.
2. Description of the Related Art
A number of important neurological diseases, including Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), and prion-mediated diseases are characterized by the deposition of aggregated proteins, referred to amyloid, in the central nervous system (CNS) (for reviews, see Glenner et al.,
J. Neurol. Sci.
94:1-28 [1989]; Haan et al.,
Clin. Neurol. Neurosurg.
92(4):305-310 [1990]). These highly insoluble aggregates are composed of nonbranching, fibrillar proteins with the common characteristic of &bgr;-pleated sheet conformation. In the CNS, amyloid can be present in cerebral and meningeal blood vessels (cerebrovascular deposits) and in the brain parenchyma (plaques). Neuropathological studies in human and animal models indicate that cells proximal to amyloid deposits are disturbed in their normal functions (Mandybur,
Acta Neuropathol.
78:329-331 [1989]; Kawai et al.,
Brain Res.
623:142-146 [1993]; Martin et al.,
Am. J. Pathol.
145:1348-1381 [1994]; Kalaria et al.,
Neuroreport
6:477-480 [1995]; Masliah et al.,
J. Neurosci.
16:5795-5811 [1996]; Selkoe,
J. Biol. Chem.
271:18295-18298 [1996]; Hardy,
Trends Neurosci
20:154-159 [1997]).
AD and CAA share biochemical and neuropathological markers, but differ somewhat in the extent and location of amyloid deposits as well as in the symptoms exhibited by affected individuals. The neurodegenerative process of AD, the most common neurodegenerative disorder worldwide, is characterized by the progressive and irreversible deafferentation of the limbic system, association neocortex, and basal forebrain accompanied by neuritic plaque and tangle formation (for a review, see Terry et al., “Structural alteration in Alzheimer's disease,” In: Alzheimer's disease, Terry et al. Eds., 1994, pp. 179-196, Raven Press, New York). Dystrophic neurites, as well as reactive astocytes and microglia, are associated with these amyloid-associated neuritic plaques. Although the neuritic population in any given plaque is mixed, the plaques generally are composed of spherical neurites that contain synaptic proteins, APP (type I), and fusiform neurites containing cytoskeletal proteins and paired helical filaments (PHF; type II).
CAA patients display various vascular syndromes, of which the most documented is cerebral parenchymal hemorrhage. Cerebral parenchymal hemorrhage is the result of extensive amyloid deposition within cerebral vessels (Hardy,
Trends Neurosci
20:154-159 [1997]; Haan et al.,
Clin. Neurol. Neurosurg.
92:305-310 [1990]; Terry et al., [1994] supra; Vinters,
Stroke
18:211-224 [1987]; Itoh et al.,
J. Neurosurgical Sci.
116:135-141 [1993]; Yamada et al.,
J. Neurol. Neruosurg. Psychiatry
56:543-547 [1993]; Greenberg et al.,
Neurology
43:2073-2079 [1993]; Levy et al.,
Science
248:1124-1126 [1990]). In some familial CAA cases, dementia was noted before the onset of hemorrhages, suggesting the possibility that cerebrovascular amyloid deposits may also interfere with cognitive functions.
Both AD and CAA are characterized by the accumulation of senile plaques in the brains of the affected individuals. The main amyloid components is the amyloid &bgr; protein (A&bgr;), also referred to as amyloid &bgr; or &bgr;-amyloid peptide, derived from proteolytic processing of the &bgr;-amyloid precursor protein, &bgr;-APP or simply APP. For review in connection with AD see, Selkoe, D. J.
Nature
399: A23-A31 (1999). A&bgr; is produced by proteolytic cleavage of an integral membrane protein, termed the &bgr;-amyloid precursor protein (&bgr;APP).
The A&bgr; peptide, which is generated from APP by two putative secretases, is present at low levels in the normal CNS and blood. Two major variants, A&bgr;
1-40
and A&bgr;
1-42
are produced by alternative carboxy-terminal truncation of APP (Selkoe et al. [1988]
Proc. Natl. Acad. Sci. USA
85:7341-7345; Selkoe [1993]
Trends Neurosci
16:403-409). A&bgr;
1-42
is the more fibrillogenic and more abundant of the two peptides in amyloid deposits of both AD and CAA. In addition to the amyloid deposits in AD cases described above, most AD cases are also associated with amyloid deposition in the vascular walls (Hardy [1997], supra; Haan et al. [1990], supra; Terry et al., [1994] supra; Vinters [1987], supra; Itoh, et al. [1993], supra; Yamada et al. [1993], supra; Greenberg et al. [1993], supra; Levy et al. [1990], supra). These vascular lesions are the hallmark of CAA, which can exist in the absence of AD.
The precise mechanisms by which neuritic plaques are formed and the relationship of plaque formation to the AD-associated, and CAA-associated neurodegenerative processes are not well defined. However, evidence indicates that dysregulated expression and/or processing of APP gene products or derivatives of these gene products are involved in the pathophysiological process leading to neurodegeneration and plaque formation. For example, missense mutations in APP are tightly linked to autosomal dominant forms of AD (Hardy [1994]
Clin. Geriatr. Med.
10:239-247; Mann et al. [1992]
Neurodegeneration
1:201-215). The role of APP in neurodegenerative diseases is further implicated by the observation that persons with Down's syndrome who carry an additional copy of the human APP (HAPP) gene on their third chromosome 21 show an overexpression of hAPP (Goodison et al. [1993]
J. Neuropathol. Exp. Neurol.
52:192-198; Oyama, et al. [1994]
J. Neurochem,
62:1062-1066) as well as a prominent tendency to develop AD-type pathology early in life (Wisniewski et al. [1985]
Ann. Neurol.
17:278-282). Mutations in A&bgr; are linked to CAA associated with hereditary cerebral hemorrhage with amyloidosis (Dutch HCHWA) (Levy, et al. [1990], supra), in which amyloid deposits preferentially occur in the cerebrovascular wall with some occurrence of diffuse plaques (Maat-Schieman et al. [1994]
Acta Neuropathol
88:371-8; Wartendorff et al. [1995]
J. Neurol. Neurosurg. Psychiatry
58:699-705). A number of HAPP point mutations that are tightly associated with the development of familial AD encode amino acid changes close to either side of the A&bgr; peptide (for a review, see, e.g., Lannfelt et al. [1994]
Biochem. Soc. Trans.
22:176-179; Clark et al. [1993]
Arch. Neurol.
50:1164-1172). Finally, in vitro studies indicate that aggregated A&bgr; can induce neurodegeneration (see, e.g., Pike et al. (1995)
J. Neurochem.
64:253-265).
APP is a glycosylated, single-membrane-spanning protein expressed in a wide variety of cells in many mammalian tissues. Examples of specific isotypes of APP which are currently known to exist in humans are the 695-amino acid polypeptide (APP695) described by Kang et al. (1987)
Nature
325:733-736, which is designated as the “normal” APP. A 751-amino acid polypeptide (APP751) has been described by Ponte et al. (1988)
Nature
331:525-527 and Tanzi et al. (1988)
Nature
331:528-530. A 770-amino acid isotype of APP (APP770) is described in Kitaguchi et al. (1988)
Nature
331:530-532. A number of specific variants of APP have also been described having mutations which can differ in both position and phenotype. A general review of such mutations is pivoted in Hardy (1992)
Nature Genet.
1:233-235. A mutation of particular interest is designated the “Swedish” mutation where the normal Lys-Met residues at positions 595 and 596 are replaced by Asn-Leu. This mutation is located directly upstream of the normal P-secre
Cordell Barbara
Liu Yu-Wang
Quon Diana Hom
Schimmöller Frauke
Gitomer Ralph
Scios Inc.
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