Astrocytes from P301S Tau mice exhibit non-canonical protein secretion and reduced morphological complexity.

Abstract

Astrocytes have important neurosupportive functions in the brain that are altered in neurodegenerative diseases by unresolved mechanisms. We showed previously that astrocytes cultured from mice transgenic for human P301S-tau (P301S-mice) recapitulate the deficit in production and secretion of thrombospondin1 (Thbs1) found in symptomatic P301S mouse brains, causing both reduced synapse formation and survival of cultured neurons. To further characterise how P301S-derived astrocytes differ from controls, we have compared the secretomes produced by cultured astrocytes from postnatal day 7/8 P301S mice (P301S-ACM) versus controls (C57-ACM) using label-free LC MS/MS. We verified that Thbs1 secretion was significantly reduced in the P301S-ACM vs C57-ACM, demonstrating the robustness of the analysis. The most notable distinction was that ~ 57% of the P301S-ACM-enriched proteins were cytoplasmic proteins linked to cellular metabolism that are not predicted to be secreted via classical or non-classical secretion pathways, whereas ~88% of C57-ACM-enriched proteins comprised classically secreted proteins enriched in extracellular matrix components. These differences may be related to the finding that P301S-derived cultured astrocytes were smaller and in vivo appeared less mature in the cortex of P301S mice. The unconventional secretion pathway that P301SACM display shares similarities with several Ab-exposed ACMs, indicating that stimuli induced by tau and Ab may induce a common adverse response pathway.