G protein-coupled receptor antagonist and its use for preventing and treating alzheimer's disease

Abstract

The invention discloses methods for screening a reagent for treating or preventing Alzheimer's disease or related neurological pathology. A method according to the invention includes the steps of: (a) activating a receptor and determining a first extent of endocytosis of the receptor, wherein the receptor is a G-protein coupled receptor that associates with presenilin-1; (b) activating the receptor under the same conditions as in step (a), in the presence of a candidate reagent, and determining a second extent of endocytosis of the receptor; (c) determining a difference between the first extent of endocytosis and the second extent of endocytosis; and (d) repeating steps (a)-(c), if the difference is less than a threshold. The invention also disclose uses of receptor antagonists for manufacturing medicaments for treating or preventing Alzheimer's disease or related neurological pathology, wherein the receptor antagonists inhibit endocytosis of a G-protein coupled receptor that associates with presenilin-1 during endocytosis.

1 . A method for treating Alzheimer's disease or related neurological pathology, comprising administering a receptor antagonist to a subject in need thereof, wherein the receptor antagonist inhibits endocytosis of a G-protein coupled receptor that associates with presenilin-1 during endocytosis. 
     
     
         2 . A method for treating Alzheimer's disease or related neurological pathology, comprising administering a reagent to a subject in need thereof, wherein the reagent interferes with association of a G-protein coupled receptor and presenilin-1 or γ-secretase. 
     
     
         3 . The method of  claim 1 , wherein the G-protein coupled receptor is at least one selected from the group consisting of a β-adrenergic receptor and a δ-opioid receptor. 
     
     
         4 . The method of  claim 3 , herein the β-adrenergic receptor is a type 2 β-adrenergic receptor (β2AR). 
     
     
         5 . The method of  claim 1 , wherein the antagonist is at least one selected from ICI 118,551, propranolol, butoxamine, and naltrindole. 
     
     
         6 . The method of  claim 1 , wherein the antagonist is ICI 118,551 or butoxamine. 
     
     
         7 . A method for preparing a reagent for treating Alzheimer's disease or related neurological pathology, comprising the following steps:
 (a) activating a receptor and determining a first extent of endocytosis of the receptor, wherein the receptor is a G-protein coupled receptor that associates with presenilin-1;   (b) activating the receptor under the same conditions as in step (a), in the presence of a candidate reagent, and determining a second extent of endocytosis of the receptor;   (c) determining a difference between the first extent of endocytosis and the second extent of endocytosis;   (d) repeating steps (a)-(c), if the difference is less than a threshold; and   (e) preparing and/or purifying the candidate reagent as a medicament for treating or preventing Alzheimer's disease or related neurological pathology.   
     
     
         8 . The method of  claim 7 , wherein the receptor is at least one selected from the group consisting of a β-adrenergic receptor and δ-opioid receptor. 
     
     
         9 . The method in accordance with  claim 8 , wherein the β-adrenergic receptor is a type 2 β-adrenergic receptor (β2AR). 
     
     
         10 . The method of  claim 7 , wherein the receptor is expressed on a cell that has been transfected with a gene encoding the receptor. 
     
     
         11 . The method of  claim 7 , wherein the determining the first extend of endocytosis and the determining the second extent of endocytosis are performed by monitoring amounts of endocytosed vesicles, presenilin-1 in endocytosed vesicles, γ-secretase activity in late endosomes or lysosomes (LEL), or Amyloid-beta (Aβ) formation. 
     
     
         12 . A method for screening a reagent for treating Alzheimer's disease or related neurological pathology, comprising the following steps:
 (a) activating a receptor and determining a first extent of endocytosis of the receptor, wherein the receptor is a G-protein coupled receptor that associates with presenilin-1;   (b) activating the receptor under the same conditions as in step (a), in the presence of a candidate reagent, and determining a second extent of endocytosis of the receptor;   (c) determining a difference between the first extent of endocytosis and the second extent of endocytosis; and   (d) repeating steps (a)-(c), if the difference is less than a threshold.   
     
     
         13 . The method of  claim 12 , wherein the receptor is at least one selected from the group consisting of a β-adrenergic receptor and δ-opioid receptor. 
     
     
         14 . The method in accordance with  claim 13 , wherein the β-adrenergic receptor is a type 2 β-adrenergic receptor (β2AR). 
     
     
         15 . The method of  claim 12 , wherein the receptor is expressed on a cell that has been transfected with a gene encoding the receptor. 
     
     
         16 . The method of  claim 12 , wherein the determining the first extend of endocytosis and the determining the second extent of endocytosis are performed by monitoring amounts of endocytosed vesicles, presenilin-1 in endocytosed vesicles, γ-secretase activity in late endosomes or lysosomes (LEL), or Amyloid-beta (Aβ) formation.