Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

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

a protein-coupled receptor and alzheimer's disease technology, applied in the direction of biocide, drug composition, instruments, etc., can solve the problems of amyloidogenic or neurotoxic app fragment accumulation, app processing disruption,

Inactive Publication Date: 2012-01-05
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
View PDF1 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017]Objectives of the present invention include providing methods for screening reagents for treating or preventing Alzheimer's disease or related neurological pathology, thereby providing reagents for treating or preventing Alzheimer's disease or related neurological pathology.

Problems solved by technology

(Xu et al., PNAS USA, 93, 4081 (1996); Marambaud et al., J. Neurochem., 67, 2616 (1996)) In any event, the above results indicate that changes in neurotransmitter levels or second messenger signaling, which may result from neuron degeneration and synapse loss in AD, can disrupt APP processing and lead to accumulation of amyloidogenic or neurotoxic APP fragments.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • G protein-coupled receptor antagonist and its use for preventing and treating alzheimer's disease
  • G protein-coupled receptor antagonist and its use for preventing and treating alzheimer's disease
  • G protein-coupled receptor antagonist and its use for preventing and treating alzheimer's disease

Examples

Experimental program
Comparison scheme
Effect test

example 3

γ-Secretase Activity is Independent of cAMP Signaling

[0067]As discussed above, once activated, GPCR (including β2AR) may induce Gs protein-dependent adenylyl cyclase activation, leading to elevated intracellular cAMP level. To delineate the molecular mechanism responsible for γ-secretase activity enhancement by β2AR activation, a novel β2AR mutant (β2AR T68F, Y132G, Y219A or β2AR TYY) incapable of Gs protein activation was used in a further study. It was found that these mutations of β2AR failed to abolish the enhancement of γ-secretase activity (FIG. 8a). This result rules out the involvement of Gs protein signaling in the β2AR effect on γ-secretase. Furthermore, cells treated with reagents such as cholera toxin (CTX), forskolin (Fsk), and dybutyl-cAMP (db-cAMP), which mimic G protein activation and cAMP level elevation, did not result in enhanced γ-secretase activity (FIG. 8b). Thus, the enhanced γ-secretase activities that result from β-adrenergic receptor activation do not invol...

example 4

Endocytosis Correlates with Enhanced γ-Secretase Activity

[0069]If the enhanced γ-secretase activity does not involve G-protein signaling nor the cAMP pathway, then what is the mechanism? As discussed above with reference to FIG. 3, GPCR (including βAR and opioid receptors) activation is often accompanied by receptor endocytosis, which can also initiate specific signaling. Whether receptor endocytosis and the associated signaling are involved in the enhanced g-secretase activity can be probed by using various inhibitors of the endocytosis pathway.

[0070]FIG. 8c shows that the effect of Iso on γ-secretase activity can be abolished by treatment with endocytosis inhibitors, such as concanavalin (Con A), hypertonic solution treatment (Suc), and potassium-depleted medium (K+ dpl). FIG. 8d shows that the Iso-induced enhancement of γ-secretase activity can be abolished by transfection with a dominant negative version of dynamin (Dyn K44A) that inhibits clathrin- or caveolin-mediated endocyto...

example 5

γ-Secretase Activity and Aβ Production Associate with Endocytic Pathway

[0073]As shown in FIG. 3, once inside the cell, the endocytic vesicles are transported to their destinations via specific endocytic pathways. The endocytic pathways involve trafficking of intracellular compartments that are regulated by Rab guanosine triphosphatases (Rab GTPase). It is known that endocytic transports from plasma membrane to early endosomes and then to LEL can be blocked by Rab5 S34N or Rab7 T22N, which are dominant negative mutants of early endosome marker Rab5 or LEL marker Rab7, respectively. As shown in FIG. 11a and FIG. 11b, expression of Rab5 S34N or Rab7 T22N in HEK293 cells abolished β2AR-stimulated enhancement of γ-secretase activity (FIG. 11a) and Aβ production (FIG. 11b). Since the Rab7 T22N transfected cells can still have endocytic vesicles transported to the early endosomes. These results suggest that the enhanced γ-secretase activity and Aβ production require the endocytic vesicles ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

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.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This is a divisional application of application Ser. No. 12 / 159,183, filed on Jun. 25, 2008, which is a national stage application of PCT / CN2006 / 003595, filed on Dec. 26, 2006, which claims priorities to Chinese application No. 200610162480.7, filed on Nov. 17, 2006, and Chinese application No. 200510112005.4, filed on Dec. 26, 20057, 2006. The present application claims priorities to all these prior applications and incorporates these prior applications by reference in their entirety.BACKGROUND OF INVENTION[0002]1. Field of the Invention[0003]The present invention relates generally to prevention or treatment of Alzheimer's disease or related neurological pathologies; particularly, it relates to the use of β-adrenergic or opioid receptor antagonists for treating Alzheimer's diseases.[0004]2. Background Art[0005]Alzheimer's Disease (AD), which is characterized by progressive dementia and personality dysfunction, is the most common neurodeg...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/485A61K31/137A61P25/00C12Q1/37G01N33/566A61P25/28A61K31/138C12Q1/02
CPCG01N33/5035G01N2800/2821G01N2500/10G01N2333/726A61P25/00A61P25/28A61P43/00
Inventor PEI, GANGNI, YANXIANGZHAO, XIAOHUI
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products