Changes in Cathepsin D and Beclin-1 mRNA and protein expression by the excitotoxin quinolinic acid in human astrocytes and neurons.
Quinolinic acid (QUIN) is an excitotoxin that has been implicated in the pathogenesis of several neurodegenerative diseases including Alzheimer's disease (AD). While QUIN has been shown to induce neuronal and astrocytic apoptosis as well as excitotoxic cell death, other mechanisms such as autophagy remain unexplored. We investigated the role of Cathepsin D (CatD) and Beclin-1 (Bc1) in QUIN-treated primary human astrocytes and neurons. We demonstrated that the expression patterns of CatD, a lysosomal aspartic protease associated with autophagy, are increased at 24 h after QUIN treatment. However, unlike CatD, the expression patterns of Bc1, a tumour suppressor protein, are significantly reduced at 24 h after QUIN treatment in both brain cell types. Furthermore, we showed that the NMDA ion channel blockers, MK801, can attenuate QUIN-induced changes CatD and Bc1 expression in both astrocytes and neurons. Taken together, these results suggest that induction of deficits in CatD and Bc1 is a significant mechanism for QUIN toxicity in glial and neuronal cells. Maintenance of autophagy may play a crucial role in neuroprotection in the setting of AD.
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia.
Nady
N
Braidy
Bruce J
BJ
Brew
Nibaldo C
NC
Inestrosa
Roger
R
Chung
Perminder
P
Sachdev
Gilles J
GJ
Guillemin
D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D000071186:Beclin-1; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology; D017378:Quinolinic Acid / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016291:Dizocilpine Maleate; D002402:Cathepsin D; D017378:Quinolinic Acid