Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells

• Published in: Nature (London) Vol. 482; no. 7384; pp. 216 - 220
• Main Authors: Israel, Mason A., Yuan, Shauna H., Bardy, Cedric, Reyna, Sol M., Mu, Yangling, Herrera, Cheryl, Hefferan, Michael P., Van Gorp, Sebastiaan, Nazor, Kristopher L., Boscolo, Francesca S., Carson, Christian T., Laurent, Louise C., Marsala, Martin, Gage, Fred H., Remes, Anne M., Koo, Edward H., Goldstein, Lawrence S. B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.02.2012; Nature Publishing Group
• Subjects: 631/532/2064/2158; 692/699/375/365/1283; Adult and adolescent clinical studies; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Astrocytes - cytology; Biological and medical sciences; Biomarkers - metabolism; Cells, Cultured; Cellular Reprogramming; Coculture Techniques; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Efficiency; Endosomes - metabolism; Enzyme Activation; Female; Fibroblasts - cytology; Fibroblasts - metabolism; Genomes; Glycogen; Glycogen Synthase Kinase 3 - metabolism; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; letter; Male; Medical sciences; Messenger RNA; Middle Aged; Models, Biological; multidisciplinary; Mutation; Neurology; Neurons; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Organic mental disorders. Neuropsychology; Peptide Fragments - metabolism; Phosphoproteins - metabolism; Phosphorylation; Phosphorylation - drug effects; Physiological aspects; Protease Inhibitors - pharmacology; Proteins; Proteolysis; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Science; Science (multidisciplinary); Stem cells; Synapsins - metabolism; Synthesis; tau Proteins - metabolism; United States; Nervous system diseases; Pluripotent cell; Alzheimer disease; Pathogenesis; Stem cell; Central nervous system disease; Degenerative disease; Models; Genetic determinism; Cerebral disorder
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature10821

Induced pluripotent stem cells are shown to be useful for studying phenotypes relevant to familial and sporadic Alzheimer’s disease, even though it can take decades for the disease to manifest in patients. Alzheimer's disease in a dish Induced pluripotent stem (iPS) cell cultures are being used as models for various genetic diseases, including Parkinson's disease and diabetes. Alzheimer's disease seems an unlikely candidate for such a technique, because it can take decades for the disease to manifest in patients. But here, Lawrence Goldstein and colleagues provide evidence that iPS cell technology can be used to study phenotypes that are relevant to familial and sporadic Alzheimer's disease. Patient-derived fibroblasts were reprogrammed as iPS cells and differentiated into neurons expressing various biochemical markers of Alzheimer's disease, including elevated amyloid-β secretion. Treatment of neurons with a γ-secretase inhibitor, a type of drug considered a candidate for Alzheimer's therapy, significantly reduced both amyloid-β and phospho-tau levels. Our understanding of Alzheimer’s disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer’s disease, both caused by a duplication of the amyloid-β precursor protein gene 1 ( APP ; termed APP Dp ), two with sporadic Alzheimer’s disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP Dp patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-β(1–40), phospho-tau(Thr 231) and active glycogen synthase kinase-3β (aGSK-3β). Neurons from APP Dp and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not γ-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3β levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-β, in GSK-3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer’s disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer’s disease, even though it can take decades for overt disease to manifest in patients.