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Aging Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Alzheimer\u2019s 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 aim of this research is to determine the impact of the <jats:italic>APOE<\/jats:italic> allele \u03b54 and <jats:italic>G206D-PSEN1<\/jats:italic> on the underlying mechanisms of Alzheimer\u2019s disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Fibroblasts from Alzheimer\u2019s patients with <jats:italic>APOE<\/jats:italic> 3\/4 + <jats:italic>G206D-PSEN1<\/jats:italic> mutation and homozygous <jats:italic>APOE<\/jats:italic> \u03b54 were used to study the effects of <jats:italic>APOE<\/jats:italic> polymorphism and <jats:italic>PSEN1<\/jats:italic> mutation on the autophagy pathway, mitochondrial network fragmentation, superoxide anion levels, lysosome clustering, and p62\/SQSTM1 levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed that the <jats:italic>APOE<\/jats:italic> allele \u03b54 in homozygosis induces mitochondrial network fragmentation that correlates with an increased colocalization with p62\/SQSTM1, probably due to an inefficient autophagy. Moreover, <jats:italic>G206D-PSEN1<\/jats:italic> mutation causes an impairment of the integrity of mitochondrial networks, triggering high superoxide anion levels and thus making <jats:italic>APOE<\/jats:italic> 3\/4 + <jats:italic>PSEN1<\/jats:italic> fibroblasts more vulnerable to cell death induced by oxidative stress. Of note, <jats:italic>PSEN1<\/jats:italic> mutation induces accumulation and clustering of lysosomes that, along with an increase of global p62\/SQSTM1, could compromise lysosomal function and, ultimately, its degradation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The findings suggest that all these modifications could eventually contribute to the neuronal degeneration that underlies the pathogenesis of Alzheimer\u2019s disease. Further research in this area may help to develop targeted therapies for the treatment of Alzheimer\u2019s disease.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2023.1087072","type":"journal-article","created":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T17:20:02Z","timestamp":1688059202000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["APOE \u03b54 allele, along with G206D-PSEN1 mutation, alters mitochondrial networks and their degradation in Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"15","author":[{"given":"Irene","family":"Costa-Laparra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Ju\u00e1rez-Escoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Vicario","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Moratalla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Garc\u00eda-Sanz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-020-00732-0","article-title":"The pleiotropic role of p53 in functional\/dysfunctional neurons: Focus on pathogenesis and diagnosis of Alzheimer\u2019s disease.","volume":"12","author":"Abate","year":"2020","journal-title":"Alzheimers Res. 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