Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – The nonhuman animal is a model for human disease
Reexamination Certificate
1998-09-08
2004-04-06
Crouch, Deborah (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
The nonhuman animal is a model for human disease
C800S003000, C800S018000, C435S006120, C435S007100
Reexamination Certificate
active
06717031
ABSTRACT:
BACKGROUND OF THE INVENTION
Transgenic animal models of Alzheimer's disease are described along with a method of using the transgenic animal models to screen for therapeutics useful for the treatment of Alzheimer's disease.
Alzheimer's disease (AD) is a degenerative disorder of the brain first described by Alios Alzheimer in 1907 after examining one of his patients who suffered drastic reduction in cognitive abilities and had generalized dementia (
The early story of Alzheimer's Disease,
edited by Bick et al. (Raven Press, New York 1987)). It is the leading cause of dementia in elderly persons. AD patients have increased problems with memory loss and intellectual functions which progress to the point where they cannot function as normal individuals. With the loss of intellectual skills the patients exhibit personality changes, socially inappropriate actions and schizophrenia (
A Guide to the Understanding of Alzheimer's Disease and Related Disorders,
edited by Jorm (New York University Press, New York 1987). AD is devastating for both victims and their families, for there is no effective palliative or preventive treatment for the inevitable neurodegeneration.
The impact of AD on society and on the national economy is enormous. It is expected that the demented elderly population in the United States will increase by 41% by the year 2000. It is expensive for the health care systems that must provide institutional and ancillary care for the AD patients at an estimated annual cost of $40 billion (Jorm (1987); Fisher, “Alzheimer's Disease”, New York Times, Aug. 23, 1989, page D1, edited by Reisberg (The Free Press, New York & London 1983)). These factors imply action must be taken to generate effective treatments for AD.
At a macroscopic level, the brains of AD patients are usually smaller, sometimes weighing less than 1,000 grams. At a microscopic level, the histopathological hallmarks of AD include neurofibrillary tangles (NFT), neuritic plaques, and degeneration of neurons. AD patients exhibit degeneration of nerve cells in the frontal and temporal cortex of the cerebral cortex, pyramidal neurons of hippocampus, neurons in the medial, medial central, and cortical nuclei of the amygdala, noradrenergic neurons in the locus coeruleus, and the neurons in the basal forebrain cholinergic system. Loss of neurons in the cholinergic system leads to a consistent deficit in cholinergic presynaptic markers in AD (Fisher (1983);
Alzheimer's Disease and Related Disorders, Research and Development
edited by Kelly (Charles C. Thomas, Springfield, Ill. 1984)). In fact, AD is defined by the neuropathology of the brain.
AD is associated with neuritic plaques measuring up to 200 &mgr;m in diameter in the cortex, hippocampus, subiculum, hippocampal gyrus, and amygdala. One of the principal constituents of neuritic plaques is amyloid, which is stained by Congo Red (Fisher (1983); Kelly (1984)). Amyloid plaques stained by Congo Red are extracellular, pink or rust-colored in bright field, and birefringent in polarized light. The plaques are composed of polypeptide fibrils and are often present around blood vessels, reducing blood supply to various neurons in the brain.
Various factors such as genetic predisposition, infectious agents, toxins, metals, and head trauma have all been suggested as possible mechanisms of AD neuropathy. However, available evidence strongly indicates that there are distinct types of genetic predispositions for AD. First, molecular analysis has provided evidence for mutations in the amyloid precursor protein (APP) gene in certain AD-stricken families (Goate et al.
Nature
349:704-706 (1991); Murrell et al.
Science
254:97-99 (1991); Chartier-Harlin et al.
Nature
353:844-846 (1991); Mullan et al.,
Nature Genet.
1:345-347 (1992)). Additional genes for dominant forms of early onset AD reside on chromosome 14 and chromosome 1 (Rogaev et al.,
Nature
376:775-778 (1995); Levy-Lahad et al.,
Science
269:973-977 (1995); Sherrington et al.,
Nature
375:754-760 (1995)). Another loci associated with AD resides on chromosome 19 and encodes a variant form of apolipoprotein E (Corder,
Science
261:921-923 (1993).
Amyloid plaques are abundantly present in AD patients and in Down's Syndrome individuals surviving to the age of 40. The overexpression of APP in Down's Syndrome is recognized as a possible cause of the development of AD in Down's patients over thirty years of age (Rumble et al.,
New England J. Med.
320:1446-1452 (1989); Mann et al.,
Neurobiol. Aging
10:397-399 (1989)). The plaques are also present in the normal aging brain, although at a lower number. These plaques are made up primarily of the amyloid &bgr; peptide (A&bgr;; sometimes also referred to in the literature as &bgr;-amyloid peptide or &bgr; peptide) (Glenner and Wong,
Biochem. Biophys. Res. Comm.
120:885-890 (1984)), which is also the primary protein constituent in cerebrovascular amyloid deposits. The amyloid is a filamentous material that is arranged in beta-pleated sheets. A&bgr; is a hydrophobic peptide comprising up to 43 amino acids. The determination of its amino acid sequence led to the cloning of the APP cDNA (Kang et al.,
Nature
325:733-735 (1987); Goldgaber et al.,
Science
235:877-880 (1987); Robakis et al.,
Proc. Natl. Acad. Sci.
84:4190-4194 (1987); Tanzi et al.,
Nature
331:528-530 (1988)) and genomic APP DNA (Lemaire et al.,
Nucl. Acids Res.
17:517-522 (1989); Yoshikai et al.,
Gene
87, 257-263 (1990)). A number of forms of APP cDNA have been identified, including the three most abundant forms, APP695, APP751, and APP770. These forms arise from a single precursor RNA by alternate splicing. The gene spans more than 175 kb with 18 exons (Yoshikai et al. (1990)). APP contains an extracellular domain, a transmembrane region and a cytoplasmic domain. A&bgr; consists of up to 28 amino acids just outside the hydrophobic transmembrane domain and up to 15 residues of this transmembrane domain. Thus, A&bgr; is a cleavage product derived from APP which is normally found in brain and other tissues such as heart, kidney and spleen. However, A&bgr; deposits are usually found in abundance only in the brain.
The larger alternate forms of APP (APP751, APP770) consist of APP695 plus one or two additional domains. APP751 consists of all 695 amino acids of APP695 plus an additional 56 amino acids which has homology to the Kunitz family of serine protease inhibitors (KPI) (Tanzi et al. (1988); Weidemann et al.,
Cell
57:115-126 (1989); Kitaguchi et al.,
Nature
331:530-532 (1988); Tanzi et al.,
Nature
329:156 (1987)). APP770 contains all 751 amino acids of APP751 and an additional 19 amino acid domain homologous to the neuron cell surface antigen OX-2 (Weidemann et al. (1989); Kitaguchi et al. (1988)). Unless otherwise noted, the amino acid positions referred to herein are the positions as they appear in APP770. The amino acid number of equivalent positions in APP695 and APP751 differ in some cases due to the absence of the OX-2 and KPI domains. By convention, the amino acid positions of all forms of APP are referenced by the equivalent positions in the APP770 form. Unless otherwise noted, this convention is followed herein. Unless otherwise noted, all forms of APP and fragments of APP, including all forms of A&bgr;, referred to herein are based on the human APP amino acid sequence. APP is post-translationally modified by the removal of the leader sequence and by the addition of sulfate and sugar groups.
Van Broeckhaven et al.,
Science
248:1120-1122 (1990), have demonstrated that the APP gene is tightly linked to hereditary cerebral hemorrhage with amyloidosis (HCHWA-D) in two Dutch families. This was confirmed by the finding of a point mutation in the APP coding region in two Dutch patients (Levy et al.,
Science
248:1124-1128 (1990)). The mutation substituted a glutamine for glutamic acid at position 22 of the A&bgr; (position 618 of APP695, or position 693 of APP770). In addition, certain families are genetically predisposed to Alzheimer
Games Kate Dora
McConlogue Lisa Claire
Rydel Russell E.
Schenk Dale Bernard
Seubert Peter Andrew
Crouch Deborah
Townsend and Townsend / and Crew LLP
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