ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2003
DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 127 citations in OpenAlex.
- APP-C31 pathology as a target in neurodegenerative diseases.Journal of biomedical science · 2026Review
- Added Value of Amyloid PET Quantification with the Centiloid Scale in Clinical Practice.AJNR. American journal of neuroradiology · 2025Article
- Cannabidiolic Acid Rescues Deficits in Hippocampal Long-Term Potentiation in Models of Alzheimer's Disease: An Electrophysiological and Proteomic Analysis.International journal of molecular sciences · 2025Article
- Endocrine Dyscrasia in the Etiology and Therapy of Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2024Review
- Pharmacological Inhibition of p-21 Activated Kinase (PAK) Restores Impaired Neurite Outgrowth and Remodeling in a Cellular Model of Down Syndrome.Neurotoxicity research · 2023Article
- Differential methylation of circRNA m6A in an APP/PS1 Alzheimer's disease mouse model.Molecular medicine reports · 2023Article
- The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype.Frontiers in neuroscience · 2023Review
- Article
- Multivariate genome wide association and network analysis of subcortical imaging phenotypes in Alzheimer's disease.BMC genomics · 2020Article
- Article
- Cytotoxic and biological effects of bulk fill composites on rat cortical neuron cells.Odontology · 2018Article
- Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Review
- Review
- Role of APP Interactions with Heterotrimeric G Proteins: Physiological Functions and Pathological Consequences.Frontiers in molecular neuroscience · 2017Review
- Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer's disease.Scientific reports · 2016Article
- The endocrine dyscrasia that accompanies menopause and andropause induces aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons into the cell cycle, neurodysfunction, neurodegeneration and cognitive disease.Hormones and behavior · 2015Review
- A Unified Hypothesis of Early- and Late-Onset Alzheimer's Disease Pathogenesis.Journal of Alzheimer's disease : JAD · 2015Review
- Lethality of PAK3 and SGK2 shRNAs to human papillomavirus positive cervical cancer cells is independent of PAK3 and SGK2 knockdown.PloS one · 2015Article
- Are there roles for brain cell senescence in aging and neurodegenerative disorders?Biogerontology · 2014Review
- Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats.Neuroscience bulletin · 2014Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
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.
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Identifiers
12890786PMC6740729W1580332068What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.