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The Journal of Neuroscience, July 30, 2003, 23(17):6914-6927

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DNA Synthesis and Neuronal Apoptosis Caused by Familial Alzheimer Disease Mutants of the Amyloid Precursor Protein Are Mediated by the p21 Activated Kinase PAK3

Donna L. McPhie,¹ Robert Coopersmith,⁵ Andrew Hines-Peralta,¹ Yuzhi Chen,¹ Kathryn J. Ivins,¹ Susan P. Manly,² Michael R. Kozlowski,³ Kim A. Neve,⁴ and Rachael L. Neve¹

¹Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, Massachusetts 02478, ²Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, ³Fifth Day Therapeutics, Inc., Poway, California 92064, ⁴Medical Research Service, Veterans Affairs Medical Center, Departments of Behavioral Neuroscience and Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97201, and ⁵Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139

Apoptotic pathways and DNA synthesis are activated in neurons in the brains of individuals with Alzheimer disease (AD). However, the signaling mechanisms that mediate these events have not been defined. We show that expression of familial AD (FAD) mutants of the amyloid precursor protein (APP) in primary neurons in culture causes apoptosis and DNA synthesis. Both the apoptosis and the DNA synthesis are mediated by the p21 activated kinase PAK3, a serine-threonine kinase that interacts with APP. A dominant-negative kinase mutant of PAK3 inhibits the neuronal apoptosis and DNA synthesis; this effect is abolished by deletion of the PAK3 APP-binding domain or by coexpression of a peptide representing this binding domain. The involvement of PAK3 specifically in FAD APP-mediated apoptosis rather than in general apoptotic pathways is suggested by the facts that a dominant-positive mutant of PAK3 does not alone cause neuronal apoptosis and that the dominant-negative mutant of PAK3 does not inhibit chemically induced apoptosis. Pertussis toxin, which inactivates the heterotrimeric G-proteins G_o and G_i, inhibits the apoptosis and DNA synthesis caused by FAD APP mutants; the apoptosis and DNA synthesis are rescued by coexpression of a pertussis toxin-insensitive G_o. FAD APP-mediated DNA synthesis precedes FAD APP-mediated apoptosis in neurons, and inhibition of neuronal entry into the cell cycle inhibits the apoptosis. These data suggest that a normal signaling pathway mediated by the interaction of APP, PAK3, and G_o is constitutively activated in neurons by FAD mutations in APP and that this activation causes cell cycle entry and consequent apoptosis.

Key words: Alzheimer disease; apoptosis; cell cycle; amyloid precursor protein; p21 activated kinase; heterotrimeric G-proteins; APP intracellular domain

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Received Feb. 11, 2003; revised Jun. 3, 2003; accepted Jun. 3, 2003.

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