Amyloid precursor protein carboxy-terminal fragments modulate G-proteins and adenylate cyclase activity in Alzheimer’s disease brain

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• 作者：Mahlapuu ; Riina ; Viht ; Kaido ; Balaspiri ; Lajos ; Bogdanovic ; Nenad ; Saar ; Kü ; lliki ; Soomets ; Ursel ; et. al.
• 关键词：Disorders of the nervous systems ; Degenerative disease ; Alzheimer’ ; s&mdash ; beta amyloid ; APP C-terminus ; G-protein ; Hippocampus ; Alzheimer’ ; s disease ; Oxidative stress
• 刊名：Molecular Brain Research
• 出版年：2003
• 出版时间：September 10, 2003
• 年：2003
• 卷：117
• 期：1
• 页码：73-82
• 全文大小：304 K

文摘

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 μM APP(639–648)–APP(657–676) (PEP1) causes a fivefold stimulation in the [³⁵S]GTPγS-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]GTPγS-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]GTPγS-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.