Clinical and experimental biomedical studies have shown that Type 2 diabetes mellitus (T2DM) can be a risk factor for Alzheimer's disease (AD), both pathologies having a high occurrence in the elderly population. Patho-histological hallmarks of AD include widespread neuronal degeneration, extracellular amyloid plaques and intracellular neurofibrillary tangles, mainly composed by amyloid beta-peptide (A?) and Tau protein, respectively. Some findings indicate that metformin, a therapeutic biguanide widely administered for T2DM therapy, increases the generation of A?, thus incrementing the risk of AD insurgence. Clarifying this interaction between metformin administration and A?, can explain the strict link between T2DM and AD. In the present work we show that metformin affects the cell viability and the metabolism of the Amyloid Precursor Protein (APP), the protein originating the A? fragment, in human neuroblastoma LAN5 cells. We found that the APP over-expression causes the formation of A? polydisperse aggregates, in a dose dependent manner. In order to understand whether metformin is also able to directly interact with A?, we performed in vitro extrinsic fluorescence and light scattering experiments by incubating the amyloid peptide with and without metformin. We found that metformin increases the lag phase and reduces the growth rate of A??kinetics thus indicating the formation of a drug-A??complex. However, the final fluorescence intensity shows that the objects formed in presence of metformin are richer in on-pathway b-structures if compared with controls. Furthermore, light scattering measurements exclude that the increased fluorescence intensity could be attributable to the occurrence of species with higher hydrodynamic radius.
Metformin in vitro affects APP processing and amyloid-beta aggregation
P Picone;S Vilasi;D Giacomazza;D Nuzzo;L Caruana;L Cristaldi;V Scafidi;PL San Biagio;Marta Di Carlo
2014
Abstract
Clinical and experimental biomedical studies have shown that Type 2 diabetes mellitus (T2DM) can be a risk factor for Alzheimer's disease (AD), both pathologies having a high occurrence in the elderly population. Patho-histological hallmarks of AD include widespread neuronal degeneration, extracellular amyloid plaques and intracellular neurofibrillary tangles, mainly composed by amyloid beta-peptide (A?) and Tau protein, respectively. Some findings indicate that metformin, a therapeutic biguanide widely administered for T2DM therapy, increases the generation of A?, thus incrementing the risk of AD insurgence. Clarifying this interaction between metformin administration and A?, can explain the strict link between T2DM and AD. In the present work we show that metformin affects the cell viability and the metabolism of the Amyloid Precursor Protein (APP), the protein originating the A? fragment, in human neuroblastoma LAN5 cells. We found that the APP over-expression causes the formation of A? polydisperse aggregates, in a dose dependent manner. In order to understand whether metformin is also able to directly interact with A?, we performed in vitro extrinsic fluorescence and light scattering experiments by incubating the amyloid peptide with and without metformin. We found that metformin increases the lag phase and reduces the growth rate of A??kinetics thus indicating the formation of a drug-A??complex. However, the final fluorescence intensity shows that the objects formed in presence of metformin are richer in on-pathway b-structures if compared with controls. Furthermore, light scattering measurements exclude that the increased fluorescence intensity could be attributable to the occurrence of species with higher hydrodynamic radius.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
