Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells
Open accessAbstract
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 (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.
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iPSC-derived neurons from individuals with AD exhibit increased production of Aβ42, active GSK-3β, phosphorylated tau, endosomal abnormalities, and oxidative stress.
“iPSC-derived neurons from individuals with AD exhibit increased production of Aβ42, active GSK-3β, phosphorylated tau, endosomal abnormalities, and oxidative stress (12–17)”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [12]
The paper’s Abstract reports increased active GSK-3β, phosphorylated tau, amyloid-β(1–40), and enlarged early endosomes in neurons from two familial AD patients and one sporadic AD patient. It does not establish increased Aβ42: the Aβ(1–42) measurements were often below the assay’s detection range. The passages found also do not report oxidative stress in these AD-derived neurons. (LLM, conf=0.91)
Experimental — accuracy not yet measuredLate-stage neuropathological features, such as formation of insoluble tau and neurodegeneration, have not been reported in iPSC-derived neurons from individuals with AD.
“but late-stage neuropathological features, such as formation of insoluble tau and neurodegeneration have not been reported.”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [12]
The paper’s discussion of early pathogenesis reports elevated phosphorylated tau, but treats neurofibrillary tangles and cell death as downstream questions rather than observed features in its iPSC-derived neurons (section labelled Abstract; page unavailable). It does not report insoluble tau or neurodegeneration in its cultures, but it does not establish the broader claim that these features had not been reported in any AD iPSC-derived neurons. (LLM, conf=0.79)
Experimental — accuracy not yet measuredSeveral neurological disease studies have reverted a disease-associated cellular phenotype in patient-derived cells by correcting the mutation, for example in MAPT.
“Several studies related to neurological disease successfully reverted a disease-associated cellular phenotype in patient-derived cells by correcting the disease-associated mutation, for example in the MAPT gene106,107.”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [106]
Multiple groups have characterized iPSC lines from donor cells from FAD and sAD patients, which show increased production of Aβ, particularly Aβ42, and tau hyperphosphorylation in comparison to iPSCs derived from age-matched non-demented controls.
“Multiple groups have characterized iPSC lines from donor cells from FAD and sAD patients, which show increased production of Aβ, particularly Aβ42, and tau hyperphosphorylation in comparison to iPSCs derived from age-matched non-demented controls [66, 82, 101, 175].”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [66]
Some iPSC lines have evidence of additional AD-associated pathology such as increased activation of GSK3β, increased number of large endosomes, and accumulation of intraneuronal Aβ oligomers.
“Some iPSC lines also have evidence of additional AD-associated pathology such as increased activation of GSK3β [66], increased number of large endosomes [66], and accumulation of intraneuronal Aβ oligomers [82].”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [66]
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- Authors
- Israel, M. A., Yuan, S. H., Bardy, C., Reyna, S. M., Mu, Y., Herrera, C., Hefferan, M. P., Van Gorp, S., Nazor, K. L., Boscolo, F. S., Carson, C. T., Laurent, L. C., Marsala, M., Gage, F. H., Remes, A. M., Koo, E. H., & Goldstein, L. S. B.
- Affiliations
- Howard Hughes Medical Institute (US)
- Salk Institute for Biological Studies (US)
- University of California San Diego (US)
- Scripps Research Institute (US)
- BD Biosciences (United States) (US)
- University of Oulu (FI)
- Corresponding author
- Goldstein, Lawrence S. B.
- ORCID
- Venue
- Nature
- Published
- 2012-01-25
- Volume
- 482
- Issue
- 7384
- Pages
- 216-220
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3338985
- OpenAlex
- W2088714934
- Cited by
- 1,253
- References
- 37
- Citations by year
- 2026: 45 · 2025: 55 · 2024: 73 · 2023: 61 · 2022: 100 · 2021: 73 · 2020: 105 · 2019: 86 · 2018: 87 · 2017: 76 · 2016: 108 · 2015: 105 · 2014: 106 · 2013: 95 · 2012: 74
- FWCI
- 81.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- (No Title)
- Funders
- Howard Hughes Medical Institute
- National Institute on Aging (P50AG005131)
- National Institute of General Medical Sciences (T32GM008666)
- National Institute of Neurological Disorders and Stroke (P30NS047101, RC1NS068705)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD001259)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, induced pluripotent stem cells, familial Alzheimer's disease, sporadic Alzheimer's disease, amyloid-beta secretion, gamma-secretase inhibitors, beta-secretase inhibitors, phosphorylated tau, glycogen synthase kinase-3β, APP proteolytic processing, iPSC-derived neurons, patient-derived fibroblasts
- MeSH terms
- Aged, 80 and over, Alzheimer Disease, Astrocytes, Cells, Cultured, Enzyme Activation, Female, Fibroblasts, Humans, Male, Middle Aged, Models, Biological, Neurons, Peptide Fragments, Phosphoproteins, Phosphorylation, Protease Inhibitors, Endosomes, Biomarkers, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Synapsins, tau Proteins, Coculture Techniques, Glycogen Synthase Kinase 3, Amyloid Precursor Protein Secretases, Induced Pluripotent Stem Cells, Proteolysis, Cellular Reprogramming
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