Method of increasing cathepsin B-induced cleavage of amyloid-β peptides
The present invention provides a method of increasing cathepsin B-induced cleavage of amyloid-β (Aβ) peptide in a cell or tissue, the method generally involving contacting the cell or tissue with an agent that increases the level of cathepsin B in the cell or tissue. The present invention further provides variant cathepsin B polypeptides that are resistant to inhibition by a cysteine protease inhibitor; as well as nucleic acids encoding the variants, and host cells comprising the nucleic acids.
1. A method of increasing cathepsin B-induced cleavage of amyloid-β (Aβ) peptide in a neuron or a glial cell, the method comprising contacting the neuron or the glial cell with an agent that increases the level of cathepsin B-induced cleavage of Aβ in the neuron or the glial cell, wherein the agent is a non-steroidal anti-inflammatory agent.
2. The method of claim 1 , wherein the cell is a neuron.
3. The method of claim 1 , wherein the cell is a glial cell.
4. The method of claim 1 , wherein the agent is indomethacin.
5. The method of claim 1 , wherein the agent is ibuprofen.
6. The method of claim 1 , wherein the agent is acetylsalicylic acid, sulindac, glucametacine, acemetacin, Nalfon, Naproxen, piroxicam, diclofenac, benoxaprofen, ketoprofen, oxaprozin, etodolac, ketorolac, or nabumetone.
7. The method of claim 1 , wherein the Aβ is Aβ 1-42 .
8. The method of claim 1 , wherein the cathepsin B catalyzes carboxyl-terminal truncation of Aβ 1-42 .
9. The method of claim 1 , wherein the Aβ is cleaved at Va 1 40 -Ile 41 , Gly 38 -Gly 39 , or Gly 33 -Leu 34 .
10. The method of claim 1 , wherein the cathepsin B generates Aβ 1-40 , Aβ 1-38 , and Aβ 1-33 .
11. A method of increasing cathepsin B-induced cleavage of amyloid-β (Aβ) peptide in a neuron or a glial cell, the method comprising contacting the neuron or the glial cell with an agent that increases the level of cathepsin B-induced cleavage of Aβ in the neuron or the glial cell, wherein the agent is a non-steroidal anti-inflammatory agent selected from ibuprofen, indomethacin, acetylsalicylic acid, sulindac, glucametacine, acemetacin, Nalfon, Naproxen, piroxicam, diclofenac, benoxaprofen, ketoprofen, oxaprozin, etodolac, ketorolac, or nabumetone.