Abeta42 LOWERING AGENTS

• US 20070253905A1
• Filed: 04/26/2007
• Published: 11/01/2007
• Est. Priority Date: 04/13/2000
• Status: Abandoned Application

• Current Assignee: Mayo Foundation For Medical Education And Research (Mayo Clinic), University of California San Diego (University of California)
• Original Assignee: Mayo Foundation For Medical Education And Research (Mayo Clinic), Regents of the University of California (University of California)
• Inventors: Golde, Todd, Koo, Edward, Weggen, Sascha
• Application Number:
  US11/740,791
• Publication Number:
  US 20070253905A1
• Time in Patent Office: Days
• US Class Current: 424/9.100
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/24 having an amino or nitro group
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 49/0008 Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2800/2821 Alzheimer
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease

Abstract

The invention provides a method of preventing, delaying, or reversing the progression of Alzheimer'"'"'s disease by administering an Aβ₄₂ lowering agent to a mammal under conditions in which levels of Aβ₄₂ are selectively reduced, levels of Aβ₃₈ are increased, and levels of Aβ₄₀ are unchanged. The invention provides methods and materials for developing and identifying Aβ₄₂ lowering agents. In addition, the invention provides methods for identifying agents that increase the risk of developing, or hasten progression of, Alzheimer'"'"'s disease. The invention also provides compositions of Aβ₄₂ lowering agents and antioxidants, Aβ₄₂ lowering agents and non-selective secretase inhibitors, as well as Aβ₄₂ lowering agents and acetylcholinesterase inhibitors. The invention also provides kits containing Aβ₄₂ lowering agents, antioxidants, non-selective secretase inhibitors, and/or acetylcholinesterase inhibitors as well as instructions related to dose regimens for Aβ₄₂ lowering agents, antioxidants, non-selective secretase inhibitors, and acetylcholinesterase inhibitors.

Claims

1. A method of identifying an Aβ

₄₂ lowering agent comprising the steps of;

(a) identifying a candidate Aβ

₄₂ lowering agent which is an NSAID, NSAID derivative, or NSAID analogue;

(b) contacting said candidate Aβ

₄₂ lowering agent with a biological composition that can produce Aβ

₄₂;

(c) comparing the level of Aβ

₄₂ in said biological composition contacted with said candidate Aβ

₄₂ lowering agent to the level of Aβ

₄₂ in a biological composition not contacted with said candidate Aβ

₄₂ lowering agent;

(d) identifying said candidate Aβ

₄₂ lowering agent as an Aβ

₄₂ lowering agent if a reduction in the level of Aβ

₄₂ in said biological composition contacted with said candidate Aβ

₄₂ lowering agent is observed when compared with the level of Aβ

₄₂ in said biological composition not contacted with said candidate Aβ

₄₂ lowering agent.

2. The method of claim 1, wherein said biological composition that can produce Aβ

₄₂ comprises a cell-free composition, an in vitro cell-based composition, or an in vivo animal-based composition.

3. The method of claim 2 wherein said biological composition is a cell-free composition.

4. The method of claim 3 wherein said cell free biological composition comprises a purified enzyme preparation, a partially purified enzyme preparation, or a cell lysate.

5. The method of claim 2, wherein said biological composition is an in vitro cell-based composition.

6. The method of claim 2, wherein said biological composition is an in vitro cell-based composition or an in vivo animal-based composition, and wherein said comparing the level of Aβ

₄₂ in said biological composition contacted with said candidate Aβ

₄₂ lowering agent to the level of Aβ

₄₂ in a biological composition not contacted with said candidate Aβ

₄₂ lowering agent comprises measuring the level secreted Aβ

₄₂.

7. The method of claim 5, wherein said in vitro cell-based biological composition is a cell culture.

8. The method of claim 5, wherein said in vitro cell-based biological composition comprises cells that express one or more familial Alzheimer'"'"'s disease genes selected from the group consisting of a mutant amyloid precursor protein (APP) gene, a mutant presenilin-1 gene, and a mutant presenilin-2 gene.

9. The method of claim 5, wherein said in vitro cell-based biological composition comprises cells that express a mutant APP having the Swedish mutation (APP695NL).

10. The method of claim 7, wherein the cells of said cell culture are capable of secreting one or more Aβ

peptides selected from the group consisting of Aβ

₃₄, Aβ

₃₆, Aβ

₃₇, Aβ

₃₈, Aβ

₃₉, Aβ

₄₀ and Aβ

₄₂.

11. The method of claim 7, wherein the cells of said cell culture can secrete Aβ

₄₂.

12. The method of claim 1, wherein the step of comparing the level of Aβ

₄₂ produced by said biological composition comprises determining the level of Aβ

₄₂ with one or more techniques selected from the group consisting of an immunoprecipitation, western hybridization, sandwich enzyme-linked immunosorbent assays (ELISA), and mass-spectrometry.

13. The method of claim 1, wherein said Aβ

₄₂ level is determined by measuring Aβ

₄₂ levels with an antibody based assay.

14. The method of claim 2 wherein said biological composition is an in vivo animal-based composition.

15. The method of claim 1 wherein said biological composition is a transgenic animal.

16. The method of claim 15 wherein said transgenic animal expresses one or more familial Alzheimer'"'"'s disease genes.

17. The method of claim 16 wherein the one or more familial Alzheimer'"'"'s disease genes are selected from a mutant APP, a mutant presenilin-1, and a mutant presenilin-2.

18. The method of claim 17 wherein the familial Alzheimer'"'"'s disease gene is APP having the Swedish mutation (APP695NL).

19. The method of claim 1, wherein said biological composition comprises mammalian cells expressing APP and can be cultured under conditions that allow for APP expression, APP processing, and Aβ

₄₂ secretion from said mammalian cells.

20. The method of claim 1, wherein said biological composition comprises a cell line that expresses an APP selected from the group consisting of APP695 and APP751.

21. The method of claim 18, wherein said cells are selected from the group consisting of CHO cells, human neuroglioma cells, fibroblast cells, HEK293 cells, and HS683 cells.

22. The method of claim 1, wherein said biological composition comprises an enzyme.

23. The method of claim 1, wherein said Aβ

₄₂ lowering agent does not substantially change the level of Aβ

₄₀.

24. The method of claim 1, wherein said Aβ

₄₂ lowering agent increases the level of one or more of Aβ

₃₄, Aβ

₃₆, Aβ

₃₇, Aβ

₃₈, and Aβ

₃₉.

26. The method of claim 1, wherein said NSAID is selected from the group consisting of amino aryl carboxylic acid derivatives, aryl acetic acid derivatives, and aryl propionic acid derivatives.

27. The method of claim 1, wherein said NSAID derivative is selected from the group consisting of a derivative of an amino aryl carboxylic acid derivative, a derivative of an aryl acetic acid derivative, and a derivative of an aryl propionic acid derivative.

28. The method of claim 1, wherein said NSAID analogue is selected from the group consisting of an analogue of an amino aryl carboxylic acid derivative, an analogue of an aryl acetic acid derivative, and an analogue of an aryl propionic acid derivative.

29. The method of claim 1, wherein said NSAID, NSAID derivative, or NSAID analogue is an NSAID, NSAID derivative or NSAID analogue of an NSAID selected from the group consisting of NPPB, mefenamic acid, APHS, reservatrol, SC560, NS398, guaiazulene, ketorolac, benzylamine, ketoprofen, fenbufen, isoixicam, tenoxicam, tolfenamic acid, acemetacin, niflumic acid, dapsone, sulindac sulfone, nimesulide, suxibuzone, acetylsalicyclic acid, salicylic acid, carprofen, celecoxib, rofecoxib, fenoprofen, flurbiprofen, ibuprofen, naproxen, sulindac, sulindac sulfide, diclofenac, piroxicam, ketoprofen, diflunisal, nabumetone, etodolac, oxaprozin, meloxicam, flufenamic acid, meclofenamic acid, and indomethacin.

30. The method of claim 1, wherein said candidate Aβ

₄₂ lowering agent is a derivative or analogue of a NSAID selected from meclofenamic acid and flufenamic acid, wherein said NSAID derivative or analogue is modified from said NSAID by altering the position of the carboxylic acid group on the phenyl ring of said NSAID, altering the position or type of substituents on the phenyl ring opposite the carboxylic acid group of said NSAID, altering the bond connecting the two phenyl rings of said NSAID, altering the carboxylic acid group of said NSAID to propionic acid or another substituent, or performing any combination of these alterations, to generate a candidate Aβ

₄₂ lowering agent.

31. The method of claim 1, wherein said candidate Aβ

₄₂ lowering agent is a derivative or analogue of a NSAID selected from fenoprofen, flurbiprofen, and carprofen, wherein said NSAID derivative or analogue is modified from said NSAID by altering the position of the propionic acid group on the phenyl ring of said NSAID, altering the position or type of substituents on the phenyl ring opposite the propionic acid group of said NSAID, altering the bond connecting the two phenyl rings of said NSAID, altering the acetic acid group of said NSAID to carboxylic acid or another substituent, or performing any combination of these alterations, to generate a candidate Aβ

₄₂ lowering agent.

32. The method of claim 1, wherein said candidate Aβ

₄₂ lowering agent is a derivative or analogue of indomethacin, wherein said indomethacin derivative or analogue is modified from said indomethacin by altering the carboxylic acid group of indomethacin to another substituent, altering the indole nitrogen to another substituent, or performing any combination of these alterations to generate a candidate Aβ

₄₂ lowering agent.

33. The method of claim 1, wherein said candidate Aβ

₄₂ lowering agent is a derivative or analogue of sulindac sulfide, wherein said sulindac sulfide derivative or analogue is modified from said sulindac sulfide by altering the methylthiol group of sulindac sulfide to another substituent, altering the propionic acid group of sulindac sulfide to another substituent, altering the fluoride moiety of sulindac sulfide to another substituent, or performing any combination of these alterations, to generate a candidate Aβ

₄₂ lowering agent.

25. A method for identifying an Aβ

₄₂ lowering agent comprising;

(a) providing a candidate Aβ

₄₂ lowering agent which is a NSAID, NSAID derivative, or NSAID analogue; and

(b) determining the effects of said candidate Aβ

₄₂ lowering agent on levels of Aβ

₄₂ in a biological composition following contact of said candidate Aβ

₄₂ lowering agent with said biological composition, wherein a decrease in the level of Aβ

₄₂ indicates that said candidate Aβ

₄₂ lowering agent is an Aβ

₄₂ lowering agent.