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. A method of inhibiting the production of Aβ comprising contacting mammalian cells expressing a β-amyloid precursor protein (β-APP) with an isolated polypeptide consisting essentially of an amino acid sequence from the N-terminal fragment of PS-1 (SEQ ID NO:2), wherein the fragment is selected from the group consisting of:
(i) DEEEDEEL (SEQ ID NO:5),
(ii) SEQ ID NO:5 further including 1-10 additional amino acids at either the N- and/or C-terminal end(s),
(iii) RRSLGHPEPLSNGRPQGNSRQWEQDEEEDEELTLKYGAK (SEQ ID NO:7),
(iv) a polypeptide that is 85% identical to SEQ ID NO:7 having 1-5 conservative amino acid substitutions,
(v) a sequence consisting of (iii) or (iv) further including 1-10 additional amino acids at the N- and/or C-terminal end(s),
(vi) DEEEDELTLKYGAK (SEQ ID NO:17),
(vii) SEQ ID NO:17 further including 1-5 conservative amino acid substitutions,
(viii) a sequence consisting of (vi) or (vii) further including 1-10 additional amino acids at the N- or C-terminus,
(ix) any of the foregoing polypeptides comprising an unnatural amino acid or D-amino acid, and
(x) combinations of any of the foregoing,
wherein the isolated polypeptide inhibits production of Aβ in a cell.
2. The method of claim 1 , wherein the isolated polypeptide consists of the amino acid sequence DEEEDEEL (SEQ ID NO:5).
3. The method of claim 1 , wherein the isolated polypeptide consists of the amino acid sequence SEQ ID NO:5 further including 1-10 additional amino acids at either the N- and/or C-terminal end(s).
4. The method of claim 1 , wherein the isolated polypeptide consists of the amino acid sequence RRSLGHPEPLSNGRPQGNSRQWEQDEEEDEELTLKYGAK (SEQ ID NO:7).
5. The method of claim 1 , wherein the isolated polypeptide is 85% identical to the amino acid sequence of SEQ ID NO:7 but has 1-5 conservative amino acid substitutions.
6. The method of claim 1 , wherein the isolated polypeptide consists of the amino acid sequence DEEEDEELTLKYGAK (SEQ ID NO:17).
7. A method of inhibiting interaction of β-amyloid precursor protein (β-APP) and presenilin-1 (PS-1) comprising contacting mammalian cells expressing β-APP and/or PS-1 with an isolated polypeptide consisting essentially of an amino acid sequence from the N-terminal fragment of PS-1 (SEQ ID NO:2), wherein the fragment is selected from the group consisting of:
(i) DEEEDEEL (SEQ ID NO:5),
(ii) SEQ ID NO:5 further including 1-10 additional amino acids at either the N- and/or C-terminal end(s),
(iii) RRSLGHPEPLSNGRPQGNSRQWEQDEEEDEELTLKYGAK (SEQ ID NO:7),
(iv) a polypeptide that is 85% identical to SEQ ID NO:7 having 1-5 conservative amino acid substitutions,
(v) a sequence consisting of (iii) or (iv) further including 1-10 additional amino acids at the N- and/or C-terminal end(s),
(vi) DEEEDELTLKYGAK (SEQ ID NO:17),
(vii) SEQ ID NO:17 further including 1-5 conservative amino acid substitutions,
(viii) a sequence consisting of (vi) or (vii) further including 1-10 additional amino acids at the N- or C-terminus,
(ix) any of the foregoing polypeptides comprising an unnatural amino acid or D-amino acid, and
(x) combinations of any of the foregoing,
wherein the isolated polypeptide inhibits interaction between β-APP and PS-1.
8. The method of claim 7 , wherein the isolated polypeptide consists of the amino acid sequence DEEEDEEL (SEQ ID NO:5).
9. The method of claim 7 , wherein the isolated polypeptide consists of the amino acid sequence RRSLGHPEPLSNGRPQGNSRQWEQDEEEDEELTLKYGAK (SEQ ID NO:7).
10. The method of claim 7 , wherein the polypeptide inhibits the production of Aβ.
11. The method of claim 7 , wherein the isolated polypeptide consists of the amino acid sequence DEEEDEELTLKYGAK (SEQ ID NO:17).