Internal KCN: Dynamics of astrocytic glutamate uptake during Alzheimer’s disease progression
We consider the molecular underpinnings for the expression of astrocytic glutamate transporters (GLT1) upon modulation of extracellular amyloid-beta (eAβ) oligomers as a mapping of Alzheimer’s disease (AD) progression. With this aim, we characterize surface vs. cell-wide GLT1 expression in astrocyte cultures for different applications of eAβ in duration and concentration. The quantification of such expression reveals different modes of trafficking of GLT1 between the surface vs. intracellular compartments. Fitting a Markov model of GLT1 trafficking with our data identifies multiple pathways for astrocytic transporter dynamics with AD advancement. To gain insights into the molecular underpinnings of such variegated trafficking, we infer synthetic single-cell gene expression profiles from the MAYO clinic cohort of AD patients. Because spatio-temporal progression of Aβ plaques in our dataset is assessed by post-mortem histologic Thal scoring, we envisage a continuum in the regulational changes of astrocytic gene expression that maps Aβ-related AD progression.