Lactic Acid Induces Aberrant Amyloid Precursor Protein Processing by Promoting Its Interaction with Endoplasmic Reticulum Chaperone Proteins
| Autor: | Guilian Xu, Kirsten A. Weigel-Van Aken, Yiwen Xiang |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Amyloid
lcsh:Medicine Endoplasmic Reticulum Biochemistry/Protein Folding Amyloid beta-Protein Precursor 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Heat shock protein mental disorders Amyloid precursor protein Aspartic Acid Endopeptidases Humans Immunoprecipitation HSP70 Heat-Shock Proteins Glycolysis Lactic Acid lcsh:Science Endoplasmic Reticulum Chaperone BiP Heat-Shock Proteins 030304 developmental biology 0303 health sciences Amyloid beta-Peptides Multidisciplinary biology Endoplasmic reticulum lcsh:R Membrane Proteins Cell Biology/Cellular Death and Stress Responses Hydrogen-Ion Concentration Peptide Fragments Lactic acid Aggresome Microscopy Fluorescence Biochemistry chemistry biology.protein lcsh:Q Amyloid Precursor Protein Secretases Neurological Disorders/Alzheimer Disease Amyloid precursor protein secretase 030217 neurology & neurosurgery Molecular Chaperones Protein Binding Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 5, Iss 11, p e13820 (2010) |
| ISSN: | 1932-6203 |
| Popis: | Background Lactic acid, a natural by-product of glycolysis, is produced at excess levels in response to impaired mitochondrial function, high-energy demand, and low oxygen availability. The enzyme involved in the production of β-amyloid peptide (Aβ) of Alzheimer's disease, BACE1, functions optimally at lower pH, which led us to investigate a potential role of lactic acid in the processing of amyloid precursor protein (APP). Methodology/Principal Findings Lactic acid increased levels of Aβ40 and 42, as measured by ELISA, in culture medium of human neuroblastoma cells (SH-SY5Y), whereas it decreased APP metabolites, such as sAPPα. In cell lysates, APP levels were increased and APP was found to interact with ER-chaperones in a perinuclear region, as determined by co-immunoprecipitation and fluorescence microscopy studies. Lactic acid had only a very modest effect on cellular pH, did increase the levels of ER chaperones Grp78 and Grp94 and led to APP aggregate formation reminiscent of aggresomes. Conclusions/Significance These findings suggest that sustained elevations in lactic acid levels could be a risk factor in amyloidogenesis related to Alzheimer's disease through enhanced APP interaction with ER chaperone proteins and aberrant APP processing leading to increased generation of amyloid peptides and APP aggregates. |
| Databáze: | OpenAIRE |
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