The contribution of astrocytes to the pathophysiology of AD (Alzheimer's disease) and the molecul... more The contribution of astrocytes to the pathophysiology of AD (Alzheimer's disease) and the molecular and signalling mechanisms that potentially underlie them are still very poorly understood. However, there is mounting evidence that calcium dysregulation in astrocytes may be playing a key role. Intercellular calcium waves in astrocyte networks in vitro can be mechanically induced after Aβ (amyloid β-peptide) treatment, and spontaneously forming intercellular calcium waves have recently been shown in vivo in an APP (amyloid precursor protein)/PS1 (presenilin 1) Alzheimer's transgenic mouse model. However, spontaneous intercellular calcium transients and waves have not been observed in vitro in isolated astrocyte cultures in response to direct Aβ stimulation in the absence of potentially confounding signalling from other cell types. Here, we show that Aβ alone at relatively low concentrations is directly able to induce intracellular calcium transients and spontaneous intercellular calcium waves in isolated astrocytes in purified cultures, raising the possibility of a potential direct effect of Aβ exposure on astrocytes in vivo in the Alzheimer's brain. Waves did not occur immediately after Aβ treatment, but were delayed by many minutes before spontaneously forming, suggesting that intracellular signalling mechanisms required sufficient time to activate before intercellular effects at the network level become evident. Furthermore, the dynamics of intercellular calcium waves were heterogeneous, with distinct radial or longitudinal propagation orientations. Lastly, we also show that changes in the expression levels of the intermediate filament proteins GFAP (glial fibrillary acidic protein) and S100B are affected by Aβ-induced calcium changes differently, with GFAP being more dependent on calcium levels than S100B.
Network signaling through astrocyte syncytiums putatively contribute to the regulation of a numbe... more Network signaling through astrocyte syncytiums putatively contribute to the regulation of a number of both physiological and pathophysiological processes in the mammalian central nervous system. As such, an understanding of the underlying mechanisms is critical to determining any roles played by signaling through astrocyte networks. Astrocyte signaling is primarily mediated by the propagation of intercellular calcium waves (ICW) in the sense that paracrine signaling results in measurable intracellular calcium transients. Although the molecular mechanisms are relatively well known, there is conflicting data regarding the mechanism by which the signal propagates through the network. Experimentally there is evidence for both a point source signaling model in which adenosine triphosphate (ATP) is released by an initially activated astrocyte only, and a regenerative signaling model in which downstream astrocytes release ATP. We modeled both conditions as a simple lumped parameter phenomenological diffusion model and show that the only possible mechanism that can accurately reproduce experimentally measured results is a dual signaling mechanism that incorporates elements of both proposed signaling models. Specifically, we were able to accurately simulate experimentally measured in vitro ICW dynamics by assuming a point source signaling model with a downstream regenerative component. These results suggest that seemingly conflicting data in the literature are actually complimentary, and represents a highly efficient and robustly engineered signaling mechanism.
The contribution of astrocytes to the pathophysiology of AD (Alzheimer's disease) and the molecul... more The contribution of astrocytes to the pathophysiology of AD (Alzheimer's disease) and the molecular and signalling mechanisms that potentially underlie them are still very poorly understood. However, there is mounting evidence that calcium dysregulation in astrocytes may be playing a key role. Intercellular calcium waves in astrocyte networks in vitro can be mechanically induced after Aβ (amyloid β-peptide) treatment, and spontaneously forming intercellular calcium waves have recently been shown in vivo in an APP (amyloid precursor protein)/PS1 (presenilin 1) Alzheimer's transgenic mouse model. However, spontaneous intercellular calcium transients and waves have not been observed in vitro in isolated astrocyte cultures in response to direct Aβ stimulation in the absence of potentially confounding signalling from other cell types. Here, we show that Aβ alone at relatively low concentrations is directly able to induce intracellular calcium transients and spontaneous intercellular calcium waves in isolated astrocytes in purified cultures, raising the possibility of a potential direct effect of Aβ exposure on astrocytes in vivo in the Alzheimer's brain. Waves did not occur immediately after Aβ treatment, but were delayed by many minutes before spontaneously forming, suggesting that intracellular signalling mechanisms required sufficient time to activate before intercellular effects at the network level become evident. Furthermore, the dynamics of intercellular calcium waves were heterogeneous, with distinct radial or longitudinal propagation orientations. Lastly, we also show that changes in the expression levels of the intermediate filament proteins GFAP (glial fibrillary acidic protein) and S100B are affected by Aβ-induced calcium changes differently, with GFAP being more dependent on calcium levels than S100B.
Network signaling through astrocyte syncytiums putatively contribute to the regulation of a numbe... more Network signaling through astrocyte syncytiums putatively contribute to the regulation of a number of both physiological and pathophysiological processes in the mammalian central nervous system. As such, an understanding of the underlying mechanisms is critical to determining any roles played by signaling through astrocyte networks. Astrocyte signaling is primarily mediated by the propagation of intercellular calcium waves (ICW) in the sense that paracrine signaling results in measurable intracellular calcium transients. Although the molecular mechanisms are relatively well known, there is conflicting data regarding the mechanism by which the signal propagates through the network. Experimentally there is evidence for both a point source signaling model in which adenosine triphosphate (ATP) is released by an initially activated astrocyte only, and a regenerative signaling model in which downstream astrocytes release ATP. We modeled both conditions as a simple lumped parameter phenomenological diffusion model and show that the only possible mechanism that can accurately reproduce experimentally measured results is a dual signaling mechanism that incorporates elements of both proposed signaling models. Specifically, we were able to accurately simulate experimentally measured in vitro ICW dynamics by assuming a point source signaling model with a downstream regenerative component. These results suggest that seemingly conflicting data in the literature are actually complimentary, and represents a highly efficient and robustly engineered signaling mechanism.
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Papers by Diana Yu