Presenilin PS1∆E9 disrupts mobility of secretory organelles in rat astrocytes

Academic Article

Abstract

  • Aim: Alzheimer's disease (AD) is largely considered a neuron-derived insult, but also involves failure of astroglia. A recent study indicated that mutated presenilin 1 (PS1M146V), a putative endoplasmic reticulum (ER) Ca2+ channel with decreased Ca2+ conductance, impairs the traffic of astroglial peptidergic vesicles. Whether other pathogenically relevant PS1 mutants, such as PS1ΔE9, which code for ER channel with putative increased Ca2+ conductance, similarly affect vesicle traffic, is unknown. Methods: Here, we cotransfected rat astrocytes with plasmids encoding mutant PS1ΔE9 and atrial natriuretic peptide or vesicular glutamate transporter 1 tagged with fluorescent proteins (pANP.emd or pVGLUT1-EGFP respectively), to microscopically examine whether alterations in vesicle mobility and Ca2+-regulated release of gliosignalling molecules manifest as a general vesicle-based defect; control cells were transfected to co-express exogenous or native wild-type PS1 and pANP.emd or pVGLUT1-EGFP. The vesicle mobility was analysed at rest and after ATP stimulation that increased intracellular calcium activity. Results: In PS1ΔE9 astrocytes, spontaneous mobility of both vesicle types was reduced (P <.001) when compared to controls. Post-stimulatory recovery of fast vesicle mobility was hampered in PS1ΔE9 astrocytes. The ATP-evoked peptide release was less efficient in PS1ΔE9 astrocytes than in the controls (P <.05), as was the pre-stimulatory mobility of these vesicles. Conclusion: Although the PS1 mutants PS1M146V and PS1ΔE9 differently affect ER Ca2+ conductance, our results revealed a common, vesicle-type indiscriminate trafficking defect in PS1ΔE9 astrocytes, indicating that reduced secretory vesicle-based signalling is a general deficit in AD astrocytes.
  • Digital Object Identifier (doi)

    Author List

  • Stenovec M; Trkov Bobnar S; Smolič T; Kreft M; Parpura V; Zorec R
  • Volume

  • 223
  • Issue

  • 2