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J. Biol. Chem., Vol. 279, Issue 8, 6455-6464, February 20, 2004

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-Secretase Activity of Presenilin 1 Regulates Acetylcholine Muscarinic Receptor-mediated Signal Transduction^*

Bogdan O. Popescu, Angel Cedazo-Minguez¶, Eirikur Benedikz, Takeshi Nishimura||, Bengt Winblad||, Maria Ankarcrona||, and Richard F. Cowburn||

From the Section of Experimental Geriatrics, Karolinska Institutet, Neurotec Department, Kliniskt Forskningscentrum, Novum, 141 86 Huddinge, Sweden and the ^||Section of Experimental Geriatrics, Karolinska Institutet, Neurotec Department, Karolinska Institutet Sumitomo Pharmaceuticals Alzheimer Center, Novum, 141 57 Huddinge, Sweden

Familial Alzheimer's disease (FAD) presenilin 1 (PS1) mutations give enhanced calcium responses upon different stimuli, attenuated capacitative calcium entry, an increased sensitivity of cells to undergo apoptosis, and increased -secretase activity. We previously showed that the FAD mutation causing an exon 9 deletion in PS1 results in enhanced basal phospholipase C (PLC) activity (Cedazo-Minguez, A., Popescu, B. O., Ankarcrona, M., Nishimura, T., and Cowburn, R. F. (2002) J. Biol. Chem. 277, 36646-36655). To further elucidate the mechanisms by which PS1 interferes with PLC-calcium signaling, we studied the effect of two other FAD PS1 mutants (M146V and L250S) and two dominant negative PS1 mutants (D257A and D385N) on basal and carbachol-stimulated phosphoinositide (PI) hydrolysis and intracellular calcium concentrations ([Ca²⁺]_i) in SH-SY5Y neuroblastoma cells. We found a significant increase in basal PI hydrolysis in PS1 M146V cells but not in PS1 L250S cells. Both PS1 M146V and PS1 L250S cells showed a significant increase in carbachol-induced [Ca²⁺]_i as compared with nontransfected or wild type PS1 transfected cells. The elevated carbachol-induced [Ca²⁺]_i signals were reversed by the PLC inhibitor neomycin, the ryanodine receptor antagonist dantrolene, the general aspartyl protease inhibitor pepstatin A, and the specific -secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester. The cells expressing either PS1 D257A or PS1 D385N had attenuated carbachol-stimulated PI hydrolysis and [Ca²⁺]_i responses. In nontransfected or PS1 wild type transfected cells, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester and pepstatin A also attenuated both carbachol-stimulated PI hydrolysis and [Ca²⁺]_i responses to levels found in PS1 D257A or PS1 D385N dominant negative cells. Our findings suggest that PS1 can regulate PLC activity and that this function is -secretase activity-dependent.

Received for publication, June 9, 2003 , and in revised form, October 10, 2003.

^* This work was supported by grants from the Alzheimerfonden, the Demensrbundet, the Gun och Bertil Stohnes Stiftelse, the Karolinska Institutets Research Fund, and the Åke Wiberg and Gamla Tjänarinnor Foundations. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally this the work.

^¶ To whom correspondence should be addressed: Karolinska Institutet, Neurotec Department, Section of Experimental Geriatrics, Novum, Kliniskt Forskningscentrum, Plan 4, S-141 86 Huddinge, Sweden. Tel.: 46-8-585-83751; Fax: 46-8-585-83880; E-mail: Angel.Cedazo-Minguez{at}neurotec.ki.se.

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