Fig. 8.

Two hypothesis of ARTAG development. (a) In the neuronal centric model, a neuron expresses the majority of the tau protein (1). The neuron releases this tau protein (2) which (after trauma or axonal breakage) may be taken up by an astrocyte (3) during the glymphatic removal of the tau protein. This leads to the accumulation of exogenous tau, and the seeding of aggregated astrocyte tau. (b) In the astrocyte centric model, most healthy astrocytes express no or very low levels of MAPT. Changes in the brain environment—from an injury, aging, disease, or a combination of factors—leads to a reactive astrocyte response (1), which may be centered around small blood vessels (2, 3). The reactive astrocytes then upregulate the expression of MAPT and increase kinase activity (4), which leads to the hyperphosphorylation and aggregation of tau (5), causing p-tau + aggregates in astrocyte cell bodies and perivascular foot processes (6)