Research Paper Volume 8, Issue 8 pp 1718—1734
Biological and biophysics aspects of metformin-induced effects: cortex mitochondrial dysfunction and promotion of toxic amyloid pre-fibrillar aggregates
- 1 Istituto di Biomedicina e Immunologia Molecolare, CNR, Palermo, Italy
- 2 Istituto di Biofisica, CNR, Palermo, Italy
- 3 Departimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, University of Palermo, Palermo, Italy
- 4 Current address: Italian Institute of Technology, Genova, Italy
Received: June 28, 2016 Accepted: July 15, 2016 Published: July 28, 2016
https://doi.org/10.18632/aging.101004How to Cite
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.