AUTHOR=Costa-Laparra Irene , Juárez-Escoto Elena , Vicario Carlos , Moratalla Rosario , García-Sanz Patricia TITLE=APOE ε4 allele, along with G206D-PSEN1 mutation, alters mitochondrial networks and their degradation in Alzheimer’s disease JOURNAL=Frontiers in Aging Neuroscience VOLUME=Volume 15 - 2023 YEAR=2023 URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2023.1087072 DOI=10.3389/fnagi.2023.1087072 ISSN=1663-4365 ABSTRACT=Alzheimer’s disease remains the most common neurodegenerative disorder, depicted mainly by memory loss and the presence in the brain of senile plaques and neurofibrillary tangles. This disease is related to several cellular alterations like the loss of synapses, neuronal death, disruption of lipid homeostasis, mitochondrial fragmentation, or raised oxidative stress. Notably, changes in the autophagic pathway have turned out to be a key factor in the early development of the disease. The present research is aimed to determine the impact of the APOE allele ε4 and a mutation in PSEN1 on these underlying mechanisms of Alzheimer’s disease. Remarkably, we observed that the APOE allele ε4 in homozygosis induces mitochondrial network fragmentation that correlates with an increased colocalization with p62/SQSTM1, probably due to an inefficient autophagy. Moreover, PSEN1 mutation causes an impairment of the integrity of mitochondrial networks, triggering high superoxide anion levels and thus making APOE 3/4 + PSEN1 fibroblasts more vulnerable to cell death induced by oxidative stress. Of note, PSEN1 mutation does induce an accumulation and clustering of lysosomes and, along with an increase of global p62/SQSTM1, could compromise lysosomal function and, ultimately, degradation. All these modifications could eventually contribute to the neuronal degeneration that underlies the pathogenesis of Alzheimer’s disease.