The high prevalence of both Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) in the elderly population suggests that concomitant pharmacotherapy could be desirable. AD is the leading cause of dementia in the ageing and is characterized by gradual loss of cognitive functions. Ageing is a primary risk factor for the development of AD, as well as for a variety of pathological conditions, such as T2DM, that can potentially obscure a diagnosis of AD or interfere with AD pharmacotherapy. 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. Clinical and experimental biomedical studies indicate that metformin, a therapeutic biguanide widely administered for T2DM therapy, rises the generation of A?, thus increasing the risk of AD insurgence. Elucidating this interaction between metformin administration and A? production, can explain the strict link between T2DM and AD. In the present work we demonstrate 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 ?-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 MODIFIES THE APP EXPRESSION IN CELL CULTURES AND THE KINETICS OF AMYLOID-BETA AGGREGATION
Picone P;Vilasi S;Giacomazza D;Nuzzo D;Caruana L;San Biagio PL;Di Carlo Marta
2014
Abstract
The high prevalence of both Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) in the elderly population suggests that concomitant pharmacotherapy could be desirable. AD is the leading cause of dementia in the ageing and is characterized by gradual loss of cognitive functions. Ageing is a primary risk factor for the development of AD, as well as for a variety of pathological conditions, such as T2DM, that can potentially obscure a diagnosis of AD or interfere with AD pharmacotherapy. 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. Clinical and experimental biomedical studies indicate that metformin, a therapeutic biguanide widely administered for T2DM therapy, rises the generation of A?, thus increasing the risk of AD insurgence. Elucidating this interaction between metformin administration and A? production, can explain the strict link between T2DM and AD. In the present work we demonstrate 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 ?-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.
