Aim: 

To investigate the oxidative and endoplasmic reticulum (ER) stress signalling pathways in Argyrophilic grain disease (AGD), as a potential mechanism involved in the pathogenesis of this tauopathy.

Methods: 

A case-control approach was used to assess the levels of several specific markers of different kinds of oxidative damage to proteins such as: glutamic and aminoadipic semialdehyde, N^e-carboxymethyl-lysine, N^e-carboxyethyl-lysine and N^e-malondialdehyde-lysine by mass spectrometry and western-blot technique. Also a proteomics study was carried out to identify specific brain proteins that were differentially modified in AGD cases and an immunohistochemistry of different markers of ER stress were performed, as well.

Results: 

An increase in the levels of varies oxidative stress biomarkers as protein carbonyl levels and lipid peroxidation products were observed in cases affected from the disease when compared to control. This finding was associated to marked changes in mitochondrial biogenesis markers, such as PGC1a and RIP-140. There are evidences of increased expression of the key molecules involved in UPR processes: IRE1, ATF6 and XBP1 as well as eIF2-a phosporylation, which were related to elevation in ER chaperones and increased ubiquitination.

Conclusion: 

These findings implicate oxidative and ER stress in the pathogenesis of AGD, that can be attributed to the mitochondrial dysfunction evidenced by disturbance in the respiratory chain function and reduced mitochondria number on account of mitochondrial biogenesis repression.