Several studies show that individuals with Type2 diabetes (T2DM) or Obesity have a two-fold greatest risk of developing Alzheimer's disease (AD). AD is the most common cause of dementia in the elderly. Pathohistological hallmarks of AD are soluble ?-amyloid (A?) oligomers or insoluble plaques or neurofibrillary tangles. A possible link between AD and T2DM /obesity could be due to long-term use of antidiabetic drugs. Some evidences indicate that metformin, the usually recommended insulin-sensitizing drug, increases the production and aggregation of A?. In this study we utilize a mouse model to investigate the ability of metformin to reach the brain by imaging studies and biochemical analysis. Metformin was administered for 3 months and an increase of the level of expression of proteins involved in AD neurodegeneration was detected. Immunofluorescence analysis with anti-A? antibodies and Th-T staining revealed presence of amyloid plaques. In order to understand whether metformin is also able to directly interact with A?, we performed in vitro extrinsic fluorescence, dynamic light scattering (DLS) circular dichroism (CD) and Atomic Force Microscopy (AFM) experiments, by incubating the amyloid peptide with and without metformin. We found that metformin increases the lag time and reduces the extent of fibrillation (ThT plateau level). From DLS experiments, these species result lower in hydrodynamic size. In addition, the typical conversion to beta structure that typically accompanies the fibril forma tion is slowed down by the presence of metformin. Finally, AFM measurements confirm that the presence of metformin sizably reduces the formation of large amyloid fibers, probably favoring the smaller aggregates. In conclusion, in vitro metformin inhibits fibrillogenesis stabilizing small oligomeric species that probably have high toxicity potential that could reflect the physiological features observed in vivo

On the direct and cell-mediated interactions between Metformin and beta-amyloid peptide

P Picone;S Vilasi;F Librizzi;D Nuzzo;L Caruana;D Giacomazza;M Di Carlo
2015

Abstract

Several studies show that individuals with Type2 diabetes (T2DM) or Obesity have a two-fold greatest risk of developing Alzheimer's disease (AD). AD is the most common cause of dementia in the elderly. Pathohistological hallmarks of AD are soluble ?-amyloid (A?) oligomers or insoluble plaques or neurofibrillary tangles. A possible link between AD and T2DM /obesity could be due to long-term use of antidiabetic drugs. Some evidences indicate that metformin, the usually recommended insulin-sensitizing drug, increases the production and aggregation of A?. In this study we utilize a mouse model to investigate the ability of metformin to reach the brain by imaging studies and biochemical analysis. Metformin was administered for 3 months and an increase of the level of expression of proteins involved in AD neurodegeneration was detected. Immunofluorescence analysis with anti-A? antibodies and Th-T staining revealed presence of amyloid plaques. In order to understand whether metformin is also able to directly interact with A?, we performed in vitro extrinsic fluorescence, dynamic light scattering (DLS) circular dichroism (CD) and Atomic Force Microscopy (AFM) experiments, by incubating the amyloid peptide with and without metformin. We found that metformin increases the lag time and reduces the extent of fibrillation (ThT plateau level). From DLS experiments, these species result lower in hydrodynamic size. In addition, the typical conversion to beta structure that typically accompanies the fibril forma tion is slowed down by the presence of metformin. Finally, AFM measurements confirm that the presence of metformin sizably reduces the formation of large amyloid fibers, probably favoring the smaller aggregates. In conclusion, in vitro metformin inhibits fibrillogenesis stabilizing small oligomeric species that probably have high toxicity potential that could reflect the physiological features observed in vivo
2015
Istituto di biomedicina e di immunologia molecolare - IBIM - Sede Palermo
9788890580581
Metformin
Alzheimer's disease
?-amyloid
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14243/308943
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