Amyloid β protein (globular assembly and uses thereof)

• US 6,218,506 B1
• Filed: 02/05/1997
• Issued: 04/17/2001
• Est. Priority Date: 02/05/1997
• Status: Expired due to Term

• Current Assignee: Northwestern University, University of Southern California
• Original Assignee: Northwestern University, University of Southern California
• Inventors: Lambert, Mary P., Krafft, Grant A., Klein, William L., Morgan, Todd, Finch, Caleb E., Barlow, Ann, Chromy, Brett A., Wals, Pat, Rozovsky, Irina
• Primary Examiner(s): Low, Christopher S. F.
• Assistant Examiner(s): Gupta, Anish
• Application Number:
  US08/796,089
• Time in Patent Office: 1,532 Days
• Field of Search: 530/324, 530/350, 514/12, 436/86
• US Class Current: 530/324
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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: C07K 14/4711 Alzheimer's disease; Amyloid plaque core protein

Abstract

The invention described in this disclosure involves a new composition of matter, amyloid beta-derived dementing ligands (ADDL'"'"'s). ADDLs consist of amyloid β peptide assembled into soluble globular non-fibrillar oligomeric structures that are capable of activating specific cellular processes. The invention further encompasses methods for assaying the formation, presence, receptor protein binding and cellular activities of ADDLs. The invention further encompasses assay methods and inhibitor molecules for cellular signaling molecules activated by ADDLs. Also described are molecules that block proteins that promote the formation of ADDLs.

Claims

1. An isolated, soluble, non-fibrillar amyloid β

protein assembly comprising 3-12 amyloid β

proteins, wherein the amyloid β

protein is the β

1-42 protein and wherein the assembly has neurotoxicity.

2. The amyloid β

protein assembly according to claim 1 wherein said protein assembly has a molecular weight of about 27 kD to about 28 kD as measured by non-denaturing gel electrophoresis.

3. The amyloid β

protein assembly according to claim 1 wherein said protein assembly has a molecular weight of about 23 kD to about 24 kD as measured by non-denaturing gel electrophoresis.

4. The amyloid β

protein assembly according to claim 1 wherein said protein assembly comprises globules with dimensions of about 4.9 nm to about 5.3 nm as measured by atomic force microscopy.

5. The amyloid β

protein assembly according to claim 1 wherein said protein assembly comprises globules with dimensions of about 5.7 nm to about 6.2 nm as measured by atomic force microscopy.

6. The amyloid β

protein assembly according to claim 1 wherein about 70% of said protein assembly comprises a mixture of globules with dimensions of about 4.9 nm to about 5.3 nm and dimensions of about 5.7 nm to about 6.2 nm, wherein the dimensions are measured by atomic force microscopy.

7. A method for assaying the effects of the amyloid β

protein assembly according to claim 1, comprising;

(a) administering said protein assembly to the hippocampus of an animal;

(b) applying an electrical stimulus; and

(c) measuring the cell body spike amplitude over time to determine the long term potentiation response.

8. The method of claim 7, wherein the long-term potentiations response of said animal is compared to the long-term potentiation response of another animal treated in the same fashion except having saline administered instead of protein assembly prior to application of the electrical stimulus.