Cited by 379Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons

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Muratore, Christina R., Rice, Heather C., Srikanth, Priya, Callahan, Dana G., Shin, Taehwan, Benjamin, Lawrence N. P., Walsh, Dominic M., Selkoe, Dennis J. +1 more·2014·Human Molecular Genetics

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by extracellular plaques containing amyloid β (Aβ)-protein and intracellular tangles containing hyperphosphorylated Tau protein. Here, we describe the generation of inducible pluripotent stem cell lines from patients harboring the London familial AD (fAD) amyloid precursor protein (APP) mutation (V717I). We examine AD-relevant phenotypes following directed differentiation to forebrain neuronal fates vulnerable in AD. We observe that over differentiation time to mature neuronal fates, APP expression and levels of Aβ increase dramatically. In both immature and mature neuronal fates, the APPV717I mutation affects both β- and γ-secretase cleavage of APP. Although the mutation lies near the γ-secretase cleavage site in the transmembrane domain of APP, we find that β-secretase cleavage of APP is elevated leading to generation of increased levels of both APPsβ and Aβ. Furthermore, we find that this mutation alters the initial cleavage site of γ-secretase, resulting in an increased generation of both Aβ42 and Aβ38. In addition to altered APP processing, an increase in levels of total and phosphorylated Tau is observed in neurons with the APPV717I mutation. We show that treatment with Aβ-specific antibodies early in culture reverses the phenotype of increased total Tau levels, implicating altered Aβ production in fAD neurons in this phenotype. These studies use human neurons to reveal previously unrecognized effects of the most common fAD APP mutation and provide a model system for testing therapeutic strategies in the cell types most relevant to disease processes.

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  • 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 [101]

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Authors
Muratore, C. R., Rice, H. C., Srikanth, P., Callahan, D. G., Shin, T., Benjamin, L. N. P., Walsh, D. M., Selkoe, D. J., & Young-Pearse, T. L.
Affiliations
Brigham and Women's Hospital (US)
Venue
Human Molecular Genetics
Published
2014-02-12
Volume
23
Issue
13
Pages
3523-3536
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
OpenAlex
W2131108668
Cited by
379
References
49
Citations by year
2026: 10 · 2025: 23 · 2024: 30 · 2023: 31 · 2022: 32 · 2021: 34 · 2020: 40 · 2019: 47 · 2018: 38 · 2017: 27 · 2016: 29 · 2015: 27 · 2014: 9
FWCI
20.45
Type
journal article
Language
en
Open access
Locations
  • Human Molecular Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Harvard Stem Cell Institute
  • National Institute on Aging (P01AG015379, R21AG042776, R37AG006173, RF1AG042776, R01AG006173)
  • National Institute of General Medical Sciences (T32GM007753)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
familial Alzheimer's disease, APP processing, amyloid-beta, tau phosphorylation, iPSC-derived neurons, forebrain neurons
MeSH terms
Alzheimer Disease, Cell Differentiation, Humans, Neurons, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Induced Pluripotent Stem Cells

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