Amyloid precursor protein protease

Details Amyloid precursor protein protease Amyloid precursor protein protease

1997-10-02

2000-07-25

Achutamurhy, Ponnathapu

Drug, bio-affecting and body treating compositions

Enzyme or coenzyme containing

Hydrolases

424 7802, 424 9462, 435 691, 435212, 435213, 435219, 435226, 4352523, 4353201, A61K 3848, C12N 948, C12N 120, C07H 2104

Patent

active

060933976

DESCRIPTION:

BRIEF SUMMARY
Alzheimer's disease is a degenerative disorder of the human brain. Clinically, it appears as a progressive dementia. Its histopathology is characterized by degeneration of neurons, gliosis, and the abnormal deposition of proteins in the brain. Proteinaceous deposits (called "amyloid") appear as neurofibrillary tangles, amyloid plaque cores, and amyloid of the congophilic angiopathy. [For a review, see, D. J. Selkoe, Neuron, 6:487-498 (1991)]
While there is no general agreement as to the chemical nature of neurofibrillary tangles, the major constituent of both the amyloid plaque cores and the amyloid of the congophilic angiopathy has been shown to be a 4500 Dalton protein originally termed .beta.-protein or amyloid A4. Throughout this document this protein is referred to as .beta.-amyloid peptide or protein.
.beta.-Amyloid peptide is proteolytically derived from a transmembrane protein, the amyloid precursor protein. Different splice forms of the amyloid precursor protein are encoded by a widely expressed gene. see, e.g., K. Beyreuther and B. Muller-Hill, Annual Reviews in Biochemistry, 58:287-307 (1989). The most abundant form of amyloid precursor protein found in the human brain contains 695 amino acid residues and is designated as APP 695. At least three other forms do exist, however, these being given the names APP 714, APP 751, and APP 770. Tanzi, et al., Nature (London), 351:328 (1988); Ponte, et al., Nature (London), 331:525 (1988); Kitaguchi, et al., Nature (London), 331:530 (1988).
The different length isoforms arise from alternative splicing from a single amyloid precursor protein gene located on chromosome 21. Goldgaber, et al., Science, 235:877 (1987).
APP 751 and APP 770 contain a 56 amino acid Kunitz imhibitor domain, which shares 40% homology with bovine pancreatic trypsin inhibitor. Both of these forms of amyloid pancreatic trypsin inhibitor. Both of these forms of amyloid precursor protein have protease inhibitory activity. Kitaguchi, et al., supra.
Studies have also been performed to examine if changes in the relative amounts of the different forms of amyloid precursor protein are responsible for amyloid accumulation. The results of such studies have been equally confusing, but have generally supported the conclusion that the relative expression levels of the Kunitz domain containing amyloid precursor proteins are elevated in Alzheimer's disease. Johnson, et al., Science, 248:854 (1990).
Recent studies have shown that amyloid precursor protein fragments extending from the N-terminus of .beta.-amyloid peptide to the C-terminus of the full length amyloid precursor protein (the "C-100 fragment") are also capable of aggregation in vitro and in transfected cells. Dyrks, et al., EMBO Journal, 7:949 (1988); Wolf, et al., EMBO Journal, 9:2079 (1990).
.beta.-amyloid peptide consists, in its longest forms, of 42 or 43 amino acid residues. J. Kang, et al., Nature (London), 325:733-736 (1987). These peptides, however, vary as to their amino-termini. C. Hilbich, et al., Journal of Molecular Biology, 218:149-163 (1991).
The enzymes responsible for the normal, non-pathological processing of amyloid precursor protein have been termed "secretases". It is believed that the net pathological accumulation of .beta.-amyloid peptide is controlled by the relative activities of the pathologic and physiologic pathways of amyloid precursor protein.
Because senile plaques are invariably surrounded by dystrophic neurites, it was proposed early that .beta.-amyloid peptide is involved in the loss of neuronal cells that occurs in Alzheimer's disease. Bruce Yankner and co-workers were the first to demonstrate that synthetic .beta.-amyloid peptide could be neurotoxic in vitro and in vivo. B. A. Yankner, et al., Science, 245:417 (1989); See, also, N. W. Kowall, et al., Proceedinas of the National Academy of Sciences, U.S.A., 88:7247 (1991).
While many of the peptides which result from the processing of amyloid precursor protein have been identified, the proteases responsible for this processing remain unidentified for the m

REFERENCES:
Hansson et al., J. Biol. Chem. 269(30) :19420-26, Jul.29, 1994.
Nelson et al. J. Neurochem. 61, 567-577 (1993).
Skytt et al. Biochem. Biophys. Res. Comm. 211(2): 586-589, Jun. 15, 1995.

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