title: Biological and biophysics aspects of metformin-induced effects: cortex mitochondrial dysfunction and promotion of toxic amyloid pre-fibrillar aggregates.
abstract: The onset of Alzheimer disease (AD) is influenced by several risk factors comprising diabetes. Within this context, antidiabetic drugs, including metformin, are investigated for their effect on AD. We report that in the C57B6/J mice, metformin is delivered to the brain where activates AMP-activated kinase (AMPK), its molecular target. This drug affects the levels of β-secretase (BACE1) and β-amyloid precursor protein (APP), promoting processing and aggregation of β-amyloid (Aβ), mainly in the cortex region. Moreover, metformin induces mitochondrial dysfunction and cell death by affecting the level and conformation of Translocase of the Outer Membrane 40 (TOM40), voltage-dependent anion-selective channels 1 (VDAC1) and hexokinase I (HKI), proteins involved in mitochondrial transport of molecules, including Aβ. By using biophysical techniques we found that metformin is able to directly interact with Aβ influencing its aggregation kinetics and features. These findings indicate that metformin induces different adverse effects, leading to an overall increase of the risk of AD onset.
authors: Istituto di Biomedicina e Immunologia Molecolare, CNR, Palermo, Italy.
authors: Pasquale
authors: P
authors: Picone
authors: Istituto di Biofisica, CNR, Palermo, Italy.
authors: Silvia
authors: S
authors: Vilasi
authors: Istituto di Biofisica, CNR, Palermo, Italy.
authors: Fabio
authors: F
authors: Librizzi
authors: Istituto di Biofisica, CNR, Palermo, Italy.|Current address: Italian Institute of Technology, Genova, Italy.
authors: Marco
authors: M
authors: Contardi
authors: Istituto di Biomedicina e Immunologia Molecolare, CNR, Palermo, Italy.
authors: Domenico
authors: D
authors: Nuzzo
authors: Istituto di Biomedicina e Immunologia Molecolare, CNR, Palermo, Italy.
authors: Luca
authors: L
authors: Caruana
authors: Departimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, University of Palermo, Palermo, Italy.
authors: Sara
authors: S
authors: Baldassano
authors: Departimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, University of Palermo, Palermo, Italy.
authors: Antonella
authors: A
authors: Amato
authors: Departimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, University of Palermo, Palermo, Italy.
authors: Flavia
authors: F
authors: Mulè
authors: Istituto di Biofisica, CNR, Palermo, Italy.
authors: Pier Luigi
authors: PL
authors: San Biagio
authors: Istituto di Biofisica, CNR, Palermo, Italy.
authors: Daniela
authors: D
authors: Giacomazza
authors: Istituto di Biomedicina e Immunologia Molecolare, CNR, Palermo, Italy.
authors: Marta
authors: M
authors: Di Carlo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007004:Hypoglycemic Agents; D008687:Metformin; D050995:Voltage-Dependent Anion Channel 1; C515658:HK1 protein, mouse; D006593:Hexokinase; D055372:AMP-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; cell degeneration; metformin; mitochondrial dysfunction; mitochondrial pores; β-amyloid aggregation