Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – The nonhuman animal is a model for human disease
Reexamination Certificate
1997-10-08
2001-01-16
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, C424S009200
Reexamination Certificate
active
06175057
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to the field of non-human, transgenic animal models of conditions associated with accumulation of amyloid polypeptides, particulary Alzheimer's and cerebral amyloid angiopathy (CAA).
BACKGROUND OF THE INVENTION
A number of important neurological diseases including Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), and prion diseases are characterized by the deposition of aggregated proteins, referred to as amyloid, in the central nervous system (CNS) (for reviews, see Glenner et al. (1989)
J. Neurol. Sci
. 94:1-28; Haan et al. (1990)
Clin. Neurol. Neurosurg
. 92(4):305-310. These highly insoluble aggregates are composed of nonbranching, fibrillar proteins with the common characteristic of a &bgr;-pleated sheet conformation. In the CNS, amyloid can be present in cerebral and meningeal blood vessels (cerebrovascular deposits) and in brain parenchyma (plaques). Neuropathological studies in human and animal models indicate that cells proximal to amyloid deposits are disturbed in their normal functions (Mandybur (1989)
Acta Neuropathol
. 78:329-331; Kawai et al. (1993)
Brain Res
. 623:142-6; Martin et al. (1994)
Am. J. Pathol
. 145:1348-1381; Kalaria et al. (1995)
Neuroreport
6:477-80; Masliah et al. (1996)
J. Neurosci
. 16:5795-5811). AD studies additionally indicate that amyloid fibrils may actually initiate neurodegeneration (Lendon et al. (1997)
J. Am. Med. Assoc
. 277:825-31; Yankner (1996)
Nat. Med
. 2:850-2; Selkoe (1996)
J. Biol. Chem
. 271:18295-8; Hardy (1997)
Trends Neurosci
. 20:154-9).
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 cause of progressive intellectual failure in aged humans, 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. (1994) “Structural alteration in Alzheimer's disease.” In: Alzheimer's disease (Terry et al. eds.), pp. 179-196. Raven Press, New York). Dystrophic neurites, as well as reactive astrocytes and microglia, are embedded in the core of these amyloid-associated neurite 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 (1997)
Trends Neurosci
. 20:154-9; Haan et al. (1990)
Clin. Neurol. Neurosurg
. 22:305-10; Terry et al., supra; Vinters (1987)
Stroke
18:211-24; Itoh et al. (1993)
J. Neurological Sci
. 116:135-41; Yamada et al. (1993)
J. Neurol. Neurosurg. Psychiatry
5:543-7; Greenberg et al. (1993)
Neurology
43:2073-9; Levy et al. (1990)
Science
2:1124-6). In some familial CAA cases, dementia was noted before the onset of hemorrhages (27), suggesting the possibility that cerebrovascular amyloid deposits may also interfere with cognitive functions.
In both AD and CAA, the main amyloid component is the amyloid &bgr; protein (A&bgr;). The A&bgr; peptide, which is generated from the amyloid &bgr; precursor protein (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., 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 disregulated expression and/or processing of APP gene products or derivatives of these gene products derivatives 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 disease 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-D)(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; Wattendorff et al. (1995)
J. Neurol. Neurosurg. Psychiatry
5:699-705). A number 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 encoded by a 19-exon gene: exons 1-13, exon 13a, and 14-18 (Yoshikai et al. (1990)
Gene
82:257-263; see
FIG. 1
for a map of the hAPP exon-intron organization of the hAPP gene). Alternative splicing of APP gene-derived transcripts results in at least 10 isoforms (Sandbrink et al. (1994)
J. Biol. Chem
. 269:1510-1517). The predominant transcripts are APP695 (exons 1-6, 9-18, not 13a), APP751 (exons 1-7, 9-18, not 13a) and APP770 (exons 1-18, not 13a). All of these encode multidomain proteins with a single membrane-spanning region. They differ in that APP751 and APP770 contain exon 7, which encodes a serine protease inhibitor domain. APP695 is a predominant form in neuronal tissue, whereas APP751 is the predominant variant elsewhere. A&bgr; amyloid is derived from that part of the protein encoded by parts of exons 16 and 17.
In three APP mutants, valine-642 in the transmembrane domain of APP(695) is replaced by isoleucine, phenylalanine, or glycine in association with dominantly inherited familial Alzheimer disease. (According to an earlier numbering system, val642 was numbered 717 and the 3 mutations were V717I, V717F, and V717G, respectively.) Yamatsuji et al. ((1996)
Science
272:1349-1352) concluded that these three mutations account for most, if not all, of the chromosome 21-linked Alzheimer disease. Suzuki et al. ((1994)
Science
264:1336-1340) suggested that these mutations may cause Alzheimer disease by altering &bgr;-APP processing in a way that is amyloidogenic. They found that the APP-717 mutations were consistently associated with a 1.5- to 1.9-fold increase in the percentage of longer A&bgr; fragments generated and that the longer fragments f
Masliah Eliezer
Mucke Lennart
Wyss-Coray Tony
Borden Paula A.
Bozicevic Field & Francis LLP
Crouch Deborah
Francis Carol L.
The Regents of the University of California
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