title: Abeta(1-42) induces abnormal alternative splicing of tau exons 2/3 in NGF-induced PC12 cells.
abstract: Protein tau plays a pivotal role in the pathophysiology of Alzheimer's disease, where its hyperphos-phorylation promotes aggregation and microtubule destabilization. Tau undergoes alternative splicing which generates six isoforms in the human brain, due to inclusion/exclusion of exons 2, 3 and 10. Dysregulation of the splicing process of tau exon 10 is sufficient to cause tauopathy and has shown to be influenced by beta-amyloid peptides, but splicing of other exons is less studied. We studied the effects of beta-amyloid(42) in the alternative splicing of tau exons 2/3 and 6, using untreated and Nerve Growth Factor-induced PC12 cells. Beta-amyloid exposure caused formed cell processes to retract in differentiated cells and altered the expression of exons 2/3 in both undifferentiated and differentiated cells. Expression of exon 6 was repressed in undifferentiated cells only. Our results suggest that beta-amyloid interferes with the splicing process of exons 2/3, favoring their exclusion and thus the expression of immature tau isoforms that are less efficient in stabilizing microtubules and may also be more prone to hyperphosphorylation. The molecular mechanism for this amyloid-tau interaction remains to be determined, but may have potential implications for the understanding of the underlying neuropathological processes in Alzheimer's disease.
authors.affiliation: Centro de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa, Veracruz, Mexico.
authors.forename: Teresa
authors.initials: T
authors.lastname: Lagunes
authors.affiliation: Centro de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa, Veracruz, Mexico.
authors.forename: Marisol
authors.initials: M
authors.lastname: Herrera-Rivero
authors.affiliation: Cuerpo Académico de Neuroquímica, Centro de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa, Veracruz, Mexico.
authors.forename: María Elena
authors.initials: ME
authors.lastname: Hernández-Aguilar
authors.affiliation: Cuerpo Académico de Neuroquímica, Centro de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa, Veracruz, Mexico.
authors.forename: Gonzalo E
authors.initials: GE
authors.lastname: Aranda-Abreu
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D005091:Exons / Q000235:genetics*; D006801:Humans; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000235:genetics*; D051381:Rats; D024801:Tauopathies / Q000235:genetics; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D020932:Nerve Growth Factor