Aβ-mediated synaptic glutamate dynamics and calcium dynamics in astrocytes associated with Alzheimer's disease

The accumulation of amyloid beta peptide (A beta) is assumed to be one of the main causes of Alzheimer's disease AD. There is increasing evidence that astrocytes are the primary targets of A beta. A beta can cause abnormal synaptic glutamate, aberrant extrasynaptic glutamate, and astrocytic calcium dysregulation through astrocyte glutamate transporters facing the synapticc left (GLT-syn), astrocyte glutamate transporters facing the extra synaptic space (GLT-ess), metabotropic glutamatereceptors in astrocytes (mGluR), N-methyl-D-aspartate receptors in astrocytes (NMDAR), and glutamatergic gliotransmitter release (Glio-Rel). However, it is difficult to experimentally identify the extent to which each pathway affects synaptic glutamate, extrasynaptic glutamate, and astrocytic calcium signaling. Motivated by these findings, this work established aconcise mathematical model of astrocyte Ca2+ dynamics, including the above A beta-mediated glutamate-related multiple pathways. The model results presented the extent to which five mechanisms acted upon by Ab affect synaptic glutamate, extrasynaptic glutamate, and astrocytic intracellular Ca2+ signals. We found that GLT-syn is the main pathway through which A beta affects synaptic glutamate. GLT-ess and Glio-Rel are the main pathways through which A beta affects extrasynaptic glutamate. GLT-syn, mGluR, and NMDAR are the main pathways through which Ab affects astrocytic intracellular Ca2+ signals. Additionally, we discovered a strong, monotonically increasing relationship between the mean glutamate con-centration and the mean Ca(2+ )oscillation amplitude (or frequency). Our results may have therapeutic implications for slowing cell death induced by the combination of glutamate imbalance and Ca(2+ )dysregulation in AD.