Assay to identify compounds that alter apolipoprotein E...

Details Assay to identify compounds that alter apolipoprotein E... Assay to identify compounds that alter apolipoprotein E...

1999-11-22

2002-08-06

Ulm, John (Department: 1646)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

C435S007210, C435S070300, C424S570000, C424S572000, C424S577000, C514S001000

Reexamination Certificate

active

06428950

ABSTRACT:

FIELD OF THE INVENTION
The invention relates generally to the diagnosis and treatment of neurological diseases and specifically to determining if a patient's microglial and/or astrocyte cells are expressing apoE and suppressing such expression.
BACKGROUND OF THE INVENTION
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 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 associated with 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
. 92:305-10; 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
56:543-7; Greenberg et al. (1993)
Neurology
43:2073-9; Levy et al. (1990)
Science
248:1124-6). 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.
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 dysregulated 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
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).
More recently, the apoE protein has been implicated in Alzheimer's disease (hereafter “AD”) and cognitive performance. Saunders et al.
Neurol
. 43:1467-1472 (1993); Corder et al.
Science
261:921-923 (1993); and Reed et al.
Arch. Neurol
. 51:1189-1192 (1994). Apolipoprotein E (ApoE) is a 34,000 molecular weight protein which is the product of a single gene on chromosome 19. ApoE-containing lipoproteins are found in the cerebrospinal fluid and appear to play a major role in lipid transport in the central nervous system (CNS). Pitas et al.
J. Biol. Chem
. 262:14352-14360 (1987). ApoE mRNA is abundant in the brain, where it is synthesized and secreted primarily by astrocytes. Elshourbagy et al.
Proc. Natl. Acad. Sci USA
82:203-207 (1985); Boyles et al.
J. Clin. Invest
. 76:1501-1513 (1985); and Pitas et al.
Biochem. Biophys. Acta
917:148-161 (1987). The liver, followed by the brain, has the highest level of apoE mRNA expression in the human body. In normal brains, the major source of apoE is from astrocytes. The source of apoE in senile plaques, however, remains unclear. El Khoury at al.,
Neurobiol. Aging
19:S81-S84 (1998); Boyles et al.,
J. Clin. Invest
. 76:1501-1513 (1985).
ApoE levels dramatically increase (about 250-fold) after peripheral nerve injury. Müller et al.
Science
228:499-501 (1985); and Ignatius et al.
Proc. Natl. Acad. Sci. USA
83:1125-1129 (1986). For CNS neuronal repair, regulation appears to occur in response to neuronal injury, although it is not clear whether the apoE secreted in response to injury is produced by neurons or by glia. (Messer-Joudrier et al., Eur. J. Neurosci. 8:265-261 (1996).
Human apoE exists in th

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