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

• DOI: 10.1523/jneurosci.23-17-06914.2003
• Publication Date: 2018-04-13T22:30:28Z
• Authors: Donna L. McPhie; Robert Coopersmith; Andrew Hines-Peralta; Yuzhi Chen; Kathryn J. Ivins; Susan P. Manly; Michael R. Kozlowski; Kim A. Neve; Rachael L. Neve
• Keywords: Neurons; 0301 basic medicine; Recombinant Fusion Proteins; Cell Cycle; Genetic Vectors; Apoptosis; DNA; Protein Serine-Threonine Kinases; Nervous System; Rats; 3. Good health; Amyloid beta-Protein Precursor; 03 medical and health sciences; Bromodeoxyuridine; Alzheimer Disease; Organ Specificity; Mutation; In Situ Nick-End Labeling; Animals; RNA, Messenger; Cells, Cultured; Genes, Dominant; Sequence Deletion

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