Session: 3

PS3-16 | Oxidative distress and Grx2 deregulation in Alzheimer disease

Mariana Holubiec

Laboratorio de Transporte Axonal y Enfermedades Neurodegenerativas. IBCN (UBA-CONICET)

From the factors proposed to be involved in Alzheimer’s disease (AD) initiation and progression(1,2), oxidative distress, caused by an increase in reactive species produced particularly in the mitochondria, has been highlighted as a highly relevant process that mediates significant protein changes affecting neuronal function(3).
Glutaredoxins (Grx) are of utmost importance for the maintenance of the reduced state of proteins involved in relevant cellular processes; being key factors in redox regulation(4,5,6). Changes in redoxins levels have been associated with oxidative distress in AD(6). To test the association of increased oxidation and intracellular dynamic defects in the progression of AD we developed human brain organoids from iPSC control and APP Swedish mutation (APPSwe)(7,8). Our characterization of AD pathology showed, in APPSwe organoids, an increase in Aβ reactive area, as well as an increase in p-Tau levels using western blot (WB) and immunostaining techniques. WB analysis of TRXs levels showed a significant decrease of Grx2 expression in APPswe organoids. This result comes hand in hand with an increase in superoxide anion levels observed in live organoids with the APPswe mutation.
Our results highlight the relevance of modeling neurological diseases using complex tissue arrangements, and point to a deregulation in redox pathways in AD, which, if modulated, could be used as a therapeutic strategy for treatment of abnormal oxidation in this complex disease.