Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Chemical modification or the reaction product thereof – e.g.,...
Reexamination Certificate
2001-05-04
2003-10-28
Kemmerer, Elizabeth (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Chemical modification or the reaction product thereof, e.g.,...
C514S002600
Reexamination Certificate
active
06639058
ABSTRACT:
I—FIELD OF THE INVENTION
Beta-amyloid peptide (&bgr;A) is a major fibrillar component of neuritic plaques in Alzheimer's disease (AD) brains and is related to the pathogenesis of the disease. The present invention concerns the discovery of the efficiency of Poly-
L
-Lysine to dissolve preformed &bgr;A fibrils in vitro. Poly-
L
-Lysine can be used as a universal dissolver of all types of oligomeric &bgr;-sheet conformation, precursor of the fibrils, and it may also serve to prevent and/or retard amyloidogenesis in vivo AD and other types of amyloid related disorders.
II—BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) is a progressive neurodegenerative disease of the elderly, characterized by memory loss and dementia. It is the most frequent cause of dementia in the elderly, accounting for more than 15 million cases worldwide. It is pathologically characterized by proteinaceous deposits in various areas of the brain, particularly in the hippocampus and cerebral cortex (1). Such deposits include extracellular amyloid plaques, composed principally of beta-amyloid (&bgr;A), and intracellular neurofibrillary tangles comprising tau protein filaments.
The &bgr;A, a 4-kDa peptide of 39-43 amino acids, is a metabolic product of a large transmembrane amino acid precursor molecule, the amyloid precursor protein (APP). APP has several isoforms generated by alternative splicing of a pre-mRNA transcribed from a single 19-exon gene located on the long arm of chromosome 21. The major transcripts are APP695, APP751 and APP770 (2,3). Certain cases of inherited AD have been shown to result from mutations in amyloid precursor protein that lead to enhanced cellular production of the amyloidotic &bgr;A
1-42
peptide which is less soluble and more amyloidogenic than the more common 40-amino acid species. The process of soluble amyloid aggregation into insoluble fibrils is associated with neurotoxicity (4-6), although it is not entirely clear how this is mediated. Furthermore, quantitative histopathology has determined that more than 80% of amyloid plaques are associated with clusters of reactive microglia. As the principal immune effector cells of the brain, activated microglia are capable of releasing cytotoxic agents such as proteolytic enzymes, cytokines, complement proteins, reactive oxygen intermediates, and nitric oxide (7,8). Then, an over-abundance of &bgr;A and its accumulation as amyloid fibrils trigger disease pathology. This premise has been strengthened greatly by recent studies showing that mutations in the presenilin proteins, which result in familial early-onset AD (9,10), cause increased production of &bgr;A
1-42
(11,12). Recently, transgenic mice overexpressing the Lys
670
-Asn, Met
671
-Leu double mutation in the APP gene have been shown to have age-related AD-like cognitive changes, amyloid plaques, raised levels of the 40-amino acid form of &bgr;-amyloid and even greater elevations of the 42/43 amino acid form of &bgr;-amyloid (13). Thus, these experiments not only provide convincing evidence that APP abnormalities can cause AD, but also have established an important resource for the exploration of therapeutic and preventing strategies.
Approaches against amyloid plaques under investigation by several laboratories are by way of identifying compounds that can dissolve preformed &bgr;A fibrils (14) and, recently, by way of immunizing with &bgr;A (15-17). In this study, we demonstrated that the Poly-
L
-Lysine is a potent dissolver of preformed &bgr;A fibrils in vitro.
III—PURPOSE OF THE INVENTION
The object of the present invention is to identify compounds that can dissolve preformed &bgr;A fibrils in vitro. Compounds effective as dissolvers of preformed &bgr;A fibrils could serve as potential therapeutic agents in the future for the treatment of AD. For such a purpose, hydrosoluble and biocompatible polymers such as Poly-
L
-Lysine and Polyethylene glycol were used.
REFERENCES:
Soto et al, Inhibition of Alzheimer's amyloidosis by peptides that prevent beta-sheet conformation. Biochem. Biophys. Res. Commun. 226:672-680, 1996.*
Schenk et al, Immunization with amyloid-beta attenuates Alzheimer disease-like pathology in the PDAPP mouse. Nature, 400:173-177, 1999.*
Bard et al, peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of alzheimer disease. Nature Medicine, 6:916-919, 2000.
Dao Mai
Kemmerer Elizabeth
Li Ruixiang
LandOfFree
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