Human iPSC-derived APOE4/4 Alzheimer´s disease astrocytes exhibit a senescent and pro-inflammatory state that compromises neuronal support
Year: 2025
Type: article
Abstract: Alzheimer´s disease (AD) is dominated by a complex cellular pathology which involves most brain cell types with glial cells increasingly recognized as playing fundamental roles in neurodegeneration. Astrocytes, which perform essential functions in preserving brain homeostasis, present a reactive phenotype in the AD brains with still unknown consequences. In this study, we generated and characterized human induced pluripotent stem cell (hiPSC)-derived astrocytes from AD patients harboring the APOE4/4 genotype, the greatest genetic risk factor for late-onset AD. Disease astrocytes showed a reactive phenotype. In addition, they showed altered mitochondrial network including perinuclear clustering of mitochondria, enhanced mitochondrial fusion and higher production of reactive oxygen species which, unexpectedly, were coincident with increased oxidative phosphorylation and glycolysis. As these mitochondrial features are related to the acquisition of cell senescence, we evaluated this at the transcriptome level and found that these AD-derived astrocytes significantly upregulated gene signatures of cellular senescence and displayed a senescence-associated secretory phenotype (SASP). To verify this finding, we observed senescence-related DNA damage response in a significant proportion of cells in the cerebral cortex of AD patients, with most of these cells being astrocytes. Finally, we confirmed that this astrocytic senescent and proinflammatory phenotype is associated with a reduced neuronal support, evidencing that APOE4/4 AD astrocytes present intrinsic features that may compromise brain homeostasis and promote neurodegeneration. Addressing the causes and consequences of this astrocytic dysfunctionality should help to elucidate novel therapeutic targets able to modify the neurodegeneration present in AD.
Source: Journal of Neuroinflammation
Authors: Laura Caceres-Palomo, Elisabeth Sanchez-Mejias, Laura Trujillo-Estrada, Juan Jose Perez-Moreno, Elba Lopez-Oliva, Tau En Lim, Leah DeFlitch, Serena H. Chang, Lucas Kampman, M. Ryan Corces, Mathew Blurton-Jones, Ines Moreno-Gonzalez, Alberto Pascual, Javier Vitorica, Juan Antonio Garcia-Leon, Antonia Gutierrez
Institutions: Andalusian Centre for Nanomedicine and Biotechnology, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Biomedical Research Networking Center on Neurodegenerative Diseases, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, University of California, Irvine, Gladstone Institutes, University of California, San Francisco, University of Washington, Fred Hutch Cancer Center, Centro de Investigación Biomédica en Red
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,090
Funders: Universidad de Málaga, Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía, Consejería de Salud y Familias, Junta de Andalucía, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, National Institutes of Health, Instituto de Salud Carlos III, National Institute on Aging, National Human Genome Research Institute
Awards: G1458362881, G2643849943, G3074460020, G4081413052, G4368695057, G4371686012, G4581640803, G4954795967, G6059291470, G6580095820, G7053806769, G750844394, G8245441353, G9000044510, G9000112075, G9000116591, G9000270796, Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease
OpenAlex ID: W4417305168