Methods for screening agents that modulate presenilin activity and A-β production
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 identifying an agent that modulates presenilin-mediated Src protein kinase activity, the method comprising:
a) contacting presenilin with β-APP under conditions that would permit binding of β-APP to presenilin;
b) prior to, simultaneously with, or subsequent to a), contacting presenilin with an agent;
c) monitoring presenilin-mediated Src protein kinase activity; and
d) determining whether the agent modulates presenilin-mediated Src protein kinase activity.
2. The method of claim 1 wherein the modulating is by inhibition of presenilin-mediated Src protein kinase activity.
3. The method of claim 1 wherein the modulating is by activating presenilin-mediated Src protein kinase activity.
4. The method of claim 1 wherein the presenilin is presenilin-1 (PS-1).
5. The method of claim 1 wherein the presenilin is presenilin-2 (PS-2).
6. The method of claim 1 , wherein the agent is selected from the group consisting of a naturally occurring or synthetic polypeptide or oligopeptide, a peptidomimetic, a small organic molecule, a polysaccharide, a lipid, a fatty acid, a polynucleotide, an RNAi or siRNA, an asRNA, and an oligonucleotide.
7. The method of claim 1 wherein the contacting is in vitro.
8. The method of claim 1 wherein the contacting is in vivo.
9. The method of claim 6 , wherein the synthetic peptide or oligopeptide is a soluble N-terminal domain of PS-1 or -2.
10. The method of claim 1 , further comprising assaying an agent identified as a modulator of presenilin-mediated Src protein kinase as an inhibitor of (i) Aβ production or (ii) the interaction of the N-terminal domain of βAPP with the N-terminal domain of PS-1 and/or PS-2 comprising contacting a cell system comprising a first cell expressing βAPP and a second cell expressing PS-1 and/or PS-2 with the agent and measuring the presence of Aβ, or the interaction of N-terminal domain of βAPP with the N-terminal domain of PS-1 and/or PS-2.