Neuronal Stem Cells from Late-Onset Alzheimer Patients Show Altered Regulation of Sirtuin 1 Depending on Apolipoprotein E Indicating Disturbed Stem Cell Plasticity

• Published in: Molecular neurobiology Vol. 61; no. 3; pp. 1562 - 1579
• Main Authors: Jung, Matthias, Jung, Juliane-Susanne, Pfeifer, Jenny, Hartmann, Carla, Ehrhardt, Toni, Abid, Chaudhry Luqman, Kintzel, Jenny, Puls, Anne, Navarrete Santos, Anne, Hollemann, Thomas, Riemann, Dagmar, Rujescu, Dan
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.03.2024; Springer Nature B.V
• Subjects: Aging; Alzheimer Disease - pathology; Alzheimer's disease; Apolipoprotein E; Apolipoprotein E3 - genetics; Apolipoprotein E4; Apolipoprotein E4 - genetics; Apolipoprotein E4 - metabolism; Apolipoproteins; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Autophagy; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Plasticity; Fibroblast growth factor 2; Humans; Inhibitory postsynaptic potentials; Neural stem cells; Neurobiology; Neurodegenerative diseases; Neurology; Neurosciences; Plasmids; Pluripotency; PTEN protein; Risk factors; SIRT1 protein; Sirtuin 1; Stem cells; Stem Cells - metabolism; Neural stem cell (NSC) plasticity; Late-onset Alzheimer’s diseases (AD); Apolipoprotein E isoform 4 (APOE4); Sirtuin 1 (SIRT1); Telomere length
• ISSN: 0893-7648; 1559-1182; 1559-1182
• DOI: 10.1007/s12035-023-03633-z

Late-onset Alzheimer’s disease (AD) is a complex multifactorial disease. The greatest known risk factor for late-onset AD is the E4 allele of the apolipoprotein E (APOE), while increasing age is the greatest known non-genetic risk factor. The cell type-specific functions of neural stem cells (NSCs), in particular their stem cell plasticity, remain poorly explored in the context of AD pathology. Here, we describe a new model that employs late-onset AD patient-derived induced pluripotent stem cells (iPSCs) to generate NSCs and to examine the role played by APOE4 in the expression of aging markers such as sirtuin 1 (SIRT1) in comparison to healthy subjects carrying APOE3. The effect of aging was investigated by using iPSC-derived NSCs from old age subjects as healthy matched controls. Transcript and protein analysis revealed that genes were expressed differently in NSCs from late-onset AD patients, e.g., exhibiting reduced autophagy-related protein 7 (ATG7), phosphatase and tensin homolog (PTEN), and fibroblast growth factor 2 (FGF2). Since SIRT1 expression differed between APOE3 and APOE4 NSCs, the suppression of APOE function in NSCs also repressed the expression of SIRT1. However, the forced expression of APOE3 by plasmids did not recover differently expressed genes. The altered aging markers indicate decreased plasticity of NSCs. Our study provides a suitable in vitro model to investigate changes in human NSCs associated with aging, APOE4, and late-onset AD.