title: Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-κB activation: Use of insulin to attenuate metformin's effect.
abstract: Clinical and experimental biomedical studies have shown Type 2 diabetes mellitus (T2DM) to be a risk factor for the development of Alzheimer's disease (AD). This study demonstrates the effect of metformin, a therapeutic biguanide administered for T2DM therapy, on β-amyloid precursor protein (APP) metabolism in in vitro, ex vivo and in vivo models. Furthermore, the protective role of insulin against metformin is also demonstrated. In LAN5 neuroblastoma cells, metformin increases APP and presenilin levels, proteins involved in AD. Overexpression of APP and presenilin 1 (Pres 1) increases APP cleavage and intracellular accumulation of β-amyloid peptide (Aβ), which, in turn, promotes aggregation of Aβ. In the experimental conditions utilized the drug causes oxidative stress, mitochondrial damage, decrease of Hexokinase-II levels and cytochrome C release, all of which lead to cell death. Several changes in oxidative stress-related genes following metformin treatment were detected by PCR arrays specific for the oxidative stress pathway. These effects of metformin were found to be antagonized by the addition of insulin, which reduced Aβ levels, oxidative stress, mitochondrial dysfunction and cell death. Similarly, antioxidant molecules, such as ferulic acid and curcumin, are able to revert metformin's effect. Comparable results were obtained using peripheral blood mononuclear cells. Finally, the involvement of NF-κB transcription factor in regulating APP and Pres 1 expression was investigated. Upon metformin treatment, NF-κB is activated and translocates from the cytoplasm to the nucleus, where it induces increased APP and Pres 1 transcription. The use of Bay11-7085 inhibitor suppressed the effect of metformin on APP and Pres 1 expression.
authors: Institute of Biomedicine and Molecular Immunology "Alberto Monroy" (IBIM), Consiglio Nazionale delle Ricerche (CNR), 90146 Palermo, Italy.
authors: Pasquale
authors: P
authors: Picone
authors: Institute of Biomedicine and Molecular Immunology "Alberto Monroy" (IBIM), Consiglio Nazionale delle Ricerche (CNR), 90146 Palermo, Italy.
authors: Domenico
authors: D
authors: Nuzzo
authors: Institute of Biomedicine and Molecular Immunology "Alberto Monroy" (IBIM), Consiglio Nazionale delle Ricerche (CNR), 90146 Palermo, Italy.
authors: Luca
authors: L
authors: Caruana
authors: Institute of Biomedicine and Molecular Immunology "Alberto Monroy" (IBIM), Consiglio Nazionale delle Ricerche (CNR), 90146 Palermo, Italy.
authors: Elisa
authors: E
authors: Messina
authors: Department of STEBICEF, University of Palermo, 90100 Palermo, Italy.
authors: Annalisa
authors: A
authors: Barera
authors: Institute of Biomedicine and Molecular Immunology "Alberto Monroy" (IBIM), Consiglio Nazionale delle Ricerche (CNR), 90146 Palermo, Italy; Department of STEBICEF, University of Palermo, 90100 Palermo, Italy.
authors: Sonya
authors: S
authors: Vasto
authors: Institute of Biomedicine and Molecular Immunology "Alberto Monroy" (IBIM), Consiglio Nazionale delle Ricerche (CNR), 90146 Palermo, Italy. Electronic address: marta.dicarlo@ibim.cnr.it.
authors: Marta
authors: M
authors: Di Carlo
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000328:Adult; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D053764:Presenilin-1 / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D007328:Insulin; D016328:NF-kappa B; D053764:Presenilin-1; D008687:Metformin; D006861:Hydrogen Peroxide; D000263:Adenylate Kinase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Alzheimer's disease; Antidiabetic drug; Antioxidant; Insulin; NF-κB; Oxidative stress