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,
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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 ...
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