Rac1 inhibition negatively regulates transcriptional activity of the amyloid precursor protein gene

• Published in: Journal of neuroscience research 2009-07, Vol.87 (9), p.2105-2114
• Main Authors: Wang, Pi-Lin, Niidome, Tetsuhiro, Akaike, Akinori, Kihara, Takeshi, Sugimoto, Hachiro
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer's disease; Aminoquinolines - pharmacology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - biosynthesis; Amyloid beta-Protein Precursor - genetics; amyloid precursor protein; Animals; Cell Line; Cells, Cultured; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Down-Regulation - genetics; Enzyme Inhibitors - pharmacology; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; hippocampal neurons; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - metabolism; Humans; Mice; Mice, Inbred ICR; Neurons - drug effects; Neurons - metabolism; Peptide Fragments - metabolism; Promoter Regions, Genetic - genetics; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors; Pyrimidines - pharmacology; Rac1; rac1 GTP-Binding Protein - antagonists & inhibitors; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; RNA, Messenger - drug effects; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; transcription; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Transfection
• ISSN: 0360-4012; 1097-4547; 1097-4547
• DOI: 10.1002/jnr.22039

Rac1, a member of the Rho family GTPases, participates in a variety of cellular functions including lamellipodia formation, actin cytoskeleton organization, cell growth, apoptosis, and neuronal development. Recent studies have implicated Rac1 in cytoskeletal abnormalities, production of reactive oxygen species, and generation of the amyloid β‐peptide (Aβ) observed in Alzheimer's disease. In this study, we examined the relationship between Rac1 and amyloid precursor protein (APP), because the abnormal proteolytic processing of APP is a pathologic feature of Alzheimer's disease. In primary hippocampal neurons, the Rac1‐specific inhibitor NSC23766 decreased both Rac1 activity and APP protein levels in a concentration‐dependent manner. To elucidate how NSC23766 decreases APP protein levels, we examined the effects of NSC23766 on APP processing, degradation, and biosynthesis. NSC23766 did not increase the levels of the proteolytic products of APP, sAPPα, Aβ40, and Aβ42. The proteasome inhibitor lactacystin did not reverse the NSC23766‐induced decrease in APP protein levels. NSC23766 did, however, decrease the levels of both APP mRNA and APP protein. Decreased levels of APP mRNA and protein were also observed when HEK293 cells were transfected with an expression vector containing a dominant‐negative Rac1 mutant or with siRNA targeting Rac1. By overexpressing progressively deleted fragments of the APP promoter in HEK293 cells, we identified a Rac1 response site at positions −233 to −41 bp in the APP promoter. Taken together, our results suggest that Rac1 regulates transcription of the APP gene in primary hippocampal neurons. © 2009 Wiley‐Liss, Inc.