Amyloid precursor protein carboxy-terminal fragments modulate G-proteins and adenylate cyclase activity in Alzheimer's disease brain.
Brain Res Mol Brain Res
; 117(1): 73-82, 2003 Sep 10.
Article
in En
| MEDLINE
| ID: mdl-14499483
ABSTRACT
The influence of three C-terminal sequences and of transmembrane domain from amyloid precursor protein (APP) on the activity of G-proteins and of the coupled cAMP-signalling system in the postmortem Alzheimer's disease (AD) and age-matched control brains was compared. 10 microM APP(639-648)-APP(657-676) (PEP1) causes a fivefold stimulation in the [35S]GTPgammaS-binding to control hippocampal G-proteins. APP(657-676) (PEP2) and APP(639-648) (PEP4) showed less pronounced stimulation whereas cytosolic APP(649-669) (PEP3) showed no regulatory activity in the [35S]GTPgammaS-binding. PEP1 also showed 1.4-fold stimulatory effect of on the high-affinity GTPase and adenylate cyclase activity in control membranes, whereas in AD hippocampal membranes the stimulatory effect of PEP1 was substantially weaker. The PEP1 stimulation of the [35S]GTPgammaS-binding to the control membranes was significantly reduced by 1.5 mM glutathione, 0.5 mM antioxidant N-acetylcysteine and, in the greatest extent, by 0.01 mM of desferrioxamine. In AD hippocampus these antioxidants revealed no remarkable reducing effect on PEP1-induced stimulation. Our results suggest that C-terminal and transmembrane APP sequences possess receptor-like G-protein activating function in human hippocampus and that abnormalities of this function contribute to AD progression. The stimulatory action of these sequences on G-protein mediated signalling suggests the region-specific formation of reactive species.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Adenylyl Cyclases
/
Amyloid beta-Protein Precursor
/
GTP-Binding Proteins
/
Alzheimer Disease
/
Hippocampus
Type of study:
Observational_studies
Limits:
Aged
/
Aged80
/
Female
/
Humans
Language:
En
Journal:
Brain Res Mol Brain Res
Journal subject:
BIOLOGIA MOLECULAR
/
CEREBRO
Year:
2003
Document type:
Article
Affiliation country:
Estonia