Methods and compositions for treating neurodegenerative disorders and Alzheimer'S disease and improving normal memory
View Patent ↗The disclosure relates generally to neurodegenerative disorders and more specifically to a group of presenilin/G-protein/c-src binding polypeptides and methods of use for modulating signaling and progression of Alzheimer's disease.
1. An isolated polypeptide consisting essentially of a fragment of an N-terminal domain of a Presenilin-1 polypeptide, said domain having a sequence from amino acid x 1 to x 2 of SEQ ID NO:2, wherein x 1 is selected from amino acid 1, 2, 3, 4, and 5 of SEQ ID NO:2 and x 2 is selected from amino acid 79, 80, 81, 82 and 83 of SEQ ID NO:2 wherein the isolated polypeptide contains an amino acid sequence selected from the group consisting of:
(i) DEEEDEEL (SEQ ID NO:5),
(ii) SEQ ID NO:5 further including 1-50 additional amino acids at either the N- or C-terminal end wherein the polypeptide inhibits cell-cell interaction, inhibits Aβ production or binds to a β-APP,
(iii) RRSLGHPEPLSNGRP (SEQ ID NO:6),
(iv) SEQ ID NO:6 further including 1-5 conservative amino acid substitutions, wherein the polypeptide inhibits cell-cell interaction, inhibits Aβ production or binds to a β-APP,
(v) a sequence of (iii) or (iv) further including 1-50 additional amino acids at the N- or C-terminus, wherein the polypeptide inhibits cell-cell interaction, inhibits Aβ production or binds to a β-APP,
(vi) RRSLGHPEPLSNGRPQGNSRQVVEQDEEEDEELTLKYGAK (SEQ ID NO:7),
(vii) SEQ ID NO:7 further including 1-5 conservative amino acid substitutions, wherein the polypeptide inhibits cell-cell interaction, inhibits Aβ production or binds to a β-APP,
(viii) a sequence consisting of (vi) or (vii) further including 1-50 additional amino acids at the N- or C-terminus, wherein the polypeptide inhibits cell-cell interaction, inhibits Aβ production or binds to a β-APP, and
(ix) any of the foregoing polypeptides comprising an unnatural amino acid or D-amino acid wherein the polypeptide inhibits cell-cell interaction, inhibits Aβ production or binds to a β-APP.
2. The isolated polypeptide of claim 1 , wherein the amino acid sequence of the polypeptide comprises from 5-80 amino acids in length and having a sequence as set forth in SEQ ID NO:2 or 4 from amino acid 1 to amino acid 80.
3. An isolated polypeptide comprising a first domain consisting of a polypeptide of claim 1 and a second domain comprising a polypeptide of interest.
4. The isolated polypeptide of claim 3 , wherein the polypeptide of interest comprises an Fc domain.
5. The isolated polypeptide of claim 3 , wherein the polypeptide of interest comprises a purification peptide.
6. An oligomer polypeptide comprising at least two polypeptides each consisting of an isolated polypeptide of claim 1 .
7. An isolated polynucleotide consisting essentially of a nucleotide sequence encoding a polypeptide of claim 1 .
8. The polynucleotide of claim 7 , wherein the polynucleotide is in an expression vector.
9. The polynucleotide of claim 7 , contained in a recombinant host cell.
10. The polynucleotide of claim 7 , wherein the polynucleotide is integrated into a host cell genome.
11. A method for expressing a polypeptide comprising culturing a recombinant host cell of claim 9 .
12. The method of claim 11 , wherein the recombinant host cell is cultured under conditions promoting expression of the polypeptide from the polynucleotide.
13. The method of claim 11 , further comprising isolating the polypeptide.
14. An isolated polypeptide produced by the method of claim 13 .