Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-05-10
2002-10-01
Saoud, Christine J. (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S731000, C514S688000, C514S692000, C424S009322
Reexamination Certificate
active
06458847
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of neurology and protein chemistry. More specifically, the present invention relates to the regulation of Alzheimer's disease related proteins and uses thereof.
2. Description of the Related Art
Alzheimer's disease is a brain disorder characterized by altered protein catabolism. From the work of several laboratories, altered protein deposition has been implicated in the formation of intracellular neurofibrillary tangles found in Alzheimer's disease. The intracellular fibrillar pathology of Alzheimer's disease is characterized by the presence of filaments having a straight or paired helical morphology (Kidd, 1963; Yagishita et al., 1981). These filaments accumulate in both the somal neurofibrillary tangles (neurofibrillary tangle)
1
and the dystrophic neuropil threads (Braak et al, 1986; Kowall and Kosik, 1987). The formation of neurofibrillary tangle and dystrophic neurites are spatially correlated (Probst et al., 1989; Yamaguchi et al., 1990), and both lesions are highly correlated with the severity of dementia (McKee et al., 1991). Filamentous inclusions of this type are also seen in Down's syndrome (Wisniewski et al., 1985), Guamanian Parkinsonism-dementia (Hirano et al., 1968), and other disease states (Wisniewski et al., 1979). In progressive supranuclear palsy, neurofibrillary tangle are composed primarily of filaments possessing the straight, unpaired morphology (Tellez-Nagel and Wisniewski, 1973: Bugiani et al., 1979). Though the death of polymer-laden neurons is evidenced by the presence of insoluble tangle remnants in the extracellular space, it is not known whether polymer masses disrupt neuronal function sufficiently to induce degeneration, or whether they merely form preferentially within neurons already involved in the necrotic process.
Straight filaments (SF) and paired helical filaments (paired helical filament) form under similar conditions, as evidenced by their co-existence within individual neurofibrillary tangle (Perry et al., 1987). Straight filaments share epitopes with paired helical filaments and copurify with paired helical filaments in protocols which exploit their resistance to SDS or protease treatments (Perry et al., 1987; Crowther, 1991). In addition, there are several reports of transitional forms of fibrils possessing stretches of straight then paired helical morphology continuous within a single filament (Wischik et al., 1985; Perry et al., 1987; Papasozomenos, 1989; Crowther, 1991). These findings and others have led to speculation that straight filaments and paired helical filaments are formed by similar mechanisms of assembly (Perry et al., 1987; Crowther, 1991; Wille et al., 1992).
The only known structural constituent of the paired helical filaments is the microtubule-associated protein tau (for a review of the normal biology of tau; see Lee, 1990). The presence of tau proteins has been demonstrated by both immunochemical means (Grundke-Iqbal et al., 1986; Kosik et al., 1986), and by sequencing of peptides extracted from paired helical filaments (Wischik et al., 1988; Kondo et al., 1988). Tau extracted from paired helical filaments contains more phosphorylated residues than tau isolated from normal brain (Hasegawa et al., 1992; Ksiezak-Reding et al., 1992), and these phosphorylations are frequently invoked as being involved in the polymerization process.
Tau purified directly from brain or from brain microtubules (MT) has been reported to form a variety of polymers resembling straight filaments or paired helical filaments. Dialysis of porcine microtubule tau for several days against 6-8 M urea produced polymers ranging in width from 5-35 nm, which included a subset resembling paired helical filaments (Montejo de Garcini et al., 1986; Montejo de Garcini and Avila, 1987). The effects of urea were attributed to deamination of glutamine residues or carbamylation of lysine residues, although producing these modifications by enzymatic or chemical means did not fully reproduce the effects of urea treatment alone. Urea treated tau was reported to assemble independent of NaCl concentration in the range of 0.1-1M. Using tau purified directly from bovine whole brain, 10 nm filaments were formed in the presence of the cross-linking enzyme, transglutaminase, under conditions optimized for enzymatic activity (Dudek and Johnson, 1993). It is unlikely that this enzyme is required for tau polymerization in vivo, however, since monomeric tau is solubilized from isolated neurofibrillary tangle (Greenberg and Davies, 1990; Lee et al., 1991). Polymer formation has also been demonstrated using bacterially expressed human recombinant tau. Two groups using deletion constructs roughly equivalent to the microtubule binding domain of tau and similar acidic conditions produced several polymer species which included a subset possessing the twisted morphology of paired helical filaments (Wille et al., 1992; Crowther et al., 1992). Full length tau constructs did not assemble under these conditions. More recently, however, using conditions of neutral pH and high ionic strength (1.25 M CH
3
CO
2
—K
+
), full length tau constructs were observed to form filaments, some of which resembled paired helical filaments (Crowther et al., 1994).
The establishment of causal relationships between the assembly of tau into straight filaments and paired helical filaments and potential modulating factors such as phosphorylation or other enzymatic or chemical treatments, would benefit from an in vitro assembly system in which these polymers can be demonstrated to form under physiologically relevant conditions. Although kinetically a relatively slow process, in vitro filament formation is observed under essentially physiological conditions.
The prior art is deficient in the lack of effective means of determining the conditions in which tau purified from rat or porcine microtubule will assemble into a homogenous population of filaments resembling straight filaments and regulating the proliferation of tau. The present invention fulfills this longstanding need and desire in the art.
SUMMARY OF THE INVENTION
In one embodiment of the present invention, there is provided a method of regulating the assembly of the protein tau in the brain of a mammal in need of such treatment comprising the step of administering to said mammal a pharmacologically effective amount of a fatty acid liberation or release inhibitor.
In another embodiment of the present invention, there is provided a method of inhibiting production of Alzheimer-type amyloidosis in a mammal comprising the step of administering to said mammal in need of such treatment an effective amount of at least one modulator of fatty acid liberation or release, said modulator capable of controlling the rate of assembly of proteins found in intracellular neurofibrillary tangles and extracellular amyloid plaques.
In still yet another embodiment of the present invention, there is provided a method of treating amyloidosis associated with Alzheimer's disease in a mammalian patient comprising the step of administering to said patient in need of such treatment an effective amount of at least one modulator of fatty acid liberation or release, said modulator capable of controlling the rate of assembly of proteins found in intracellular neurofibrillary tangles and extracellular amyloid plaques.
In another embodiment of the present invention, there is provided a method of stimulating polymerization of a tau protein, comprising the step of contacting said protein with a unesterified fatty acids.
In another embodiment of the present invention, there is provided a method of stimulating polymerization of a amyloid peptide, comprising the step of contacting said peptide with a fatty acid.
Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention given for the purpose of disclosure.
REFERENCES:
patent
Binder Lester T.
Wilson David M.
Chernyshev Olga N.
Fitch Even Tabin & Flannery
Saoud Christine J.
University of Alabama at Birmingham Research Foundation
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