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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.
AuthorsTeresa Lagunes, Marisol Herrera-Rivero, María Elena Hernández-Aguilar, Gonzalo E Aranda-Abreu
JournalAnais da Academia Brasileira de Ciencias (An Acad Bras Cienc) Vol. 86 Issue 4 Pg. 1927-34 (Dec 2014) ISSN: 1678-2690 [Electronic] Brazil
PMID25590729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Amyloid beta-Peptides
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Nerve Growth Factor
Topics
  • Alternative Splicing (genetics)
  • Alzheimer Disease (genetics, metabolism)
  • Amyloid beta-Peptides (genetics)
  • Animals
  • Brain (metabolism)
  • Exons (genetics)
  • Humans
  • Nerve Growth Factor (genetics, metabolism)
  • PC12 Cells
  • Peptide Fragments (genetics)
  • Rats
  • Tauopathies (genetics)
  • tau Proteins (genetics, metabolism)

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