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, Robert Coopersmith, Andrew Hines-Peralta, Yuzhi Chen, Kathryn J. Ivins, Susan P. Manly, Michael R. Kozlowski, Kim Neve, Rachael L. Neve

Research output: Contribution to journalArticle

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Abstract

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 Go and Gi, 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 Go. 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 Go is constitutively activated in neurons by FAD mutations in APP and that this activation causes cell cycle entry and consequent apoptosis.

Original languageEnglish (US)
Pages (from-to)6914-6927
Number of pages14
JournalJournal of Neuroscience
Volume23
Issue number17
StatePublished - Jul 30 2003

Fingerprint

p21-Activated Kinases
Amyloid beta-Protein Precursor
Alzheimer Disease
Apoptosis
DNA
Neurons
Pertussis Toxin
Cell Cycle
Gi-Go GTP-Binding Protein alpha Subunits
Heterotrimeric GTP-Binding Proteins
Protein-Serine-Threonine Kinases
Amyloid
Protein Binding

Keywords

  • Alzheimer disease
  • Amyloid precursor protein
  • Apoptosis
  • APP intracellular domain
  • Cell cycle
  • Heterotrimeric G-proteins
  • P21 activated kinase

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

McPhie, D. L., Coopersmith, R., Hines-Peralta, A., Chen, Y., Ivins, K. J., Manly, S. P., ... Neve, R. L. (2003). DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. Journal of Neuroscience, 23(17), 6914-6927.

DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. / McPhie, Donna L.; Coopersmith, Robert; Hines-Peralta, Andrew; Chen, Yuzhi; Ivins, Kathryn J.; Manly, Susan P.; Kozlowski, Michael R.; Neve, Kim; Neve, Rachael L.

In: Journal of Neuroscience, Vol. 23, No. 17, 30.07.2003, p. 6914-6927.

Research output: Contribution to journalArticle

McPhie, DL, Coopersmith, R, Hines-Peralta, A, Chen, Y, Ivins, KJ, Manly, SP, Kozlowski, MR, Neve, K & Neve, RL 2003, 'DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3', Journal of Neuroscience, vol. 23, no. 17, pp. 6914-6927.
McPhie, Donna L. ; Coopersmith, Robert ; Hines-Peralta, Andrew ; Chen, Yuzhi ; Ivins, Kathryn J. ; Manly, Susan P. ; Kozlowski, Michael R. ; Neve, Kim ; Neve, Rachael L. / DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. In: Journal of Neuroscience. 2003 ; Vol. 23, No. 17. pp. 6914-6927.
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AU - Coopersmith, Robert

AU - Hines-Peralta, Andrew

AU - Chen, Yuzhi

AU - Ivins, Kathryn J.

AU - Manly, Susan P.

AU - Kozlowski, Michael R.

AU - Neve, Kim

AU - Neve, Rachael L.

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