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Recapitulation of plaque formation, tau pathology, and neurodegeneration in a human 3D matrix model of Alzheimer's disease.

Overview

Authors: Matthias Hebisch1,2, Viola Kamin1, Giovanna Cenini1, Antonia Piazzesi3, Fabio Bertan3, Beatrice Weykopf1,4, Julia Schlee1, Senthilvelrajan Kaniyappan5, Kevin J Washicosky2, Doo Yeon Kim2, Daniele Bano3, Michael Peitz1,6, Oliver Brüstle1
  1. Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty & University Hospital Bonn, 53127 Bonn, Germany
  2. Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
  3. German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
  4. Cellomics Department, LIFE & BRAIN GmbH, 53127 Bonn, Germany
  5. Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
  6. Cell Programming Core Facility, University of Bonn, 53127 Bonn, Germany
Journal: Cell reports methods, volume 6, issue 4, article 101365
Dates: received 29 April 2025; accepted 19 February 2026; published online 30 March 2026; in print April 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.crmeth.2026.101365 · PMID 41916306 · PMCID PMC13106978 · OpenAlex W7143355715
Open access: gold, a free copy (OpenAlex)
Status: code on request (how the code is found and verified)
Categories: human (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials
Keywords: Alzheimer, 3D cell culture, disease modeling, human stem cells, plaque, tangle
MeSH: Alzheimer Disease*, Models, Biological*, Plaque, Amyloid*, tau Proteins*, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Cell Differentiation, Humans, Induced Pluripotent Stem Cells, Microglia, Mitochondria, Neural Stem Cells, Presenilin-1 (* major topic)
Topic: Alzheimer's disease research and treatments (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Funding: Federal Ministry of Education and Research Bonn Office (01EK1603A-Neuro2D3); European Federation of Pharmaceutical Industries and Associations (115975); Innovative Medicines Initiative; Cure Alzheimer's Fund (2023A069137); Horizon 2020 Framework Programme; Roche; Universität Bonn
Citations: not cited yet (Europe PMC); 75 references in the paper
Research resources: Rabbit oligomer A11 polyclonal Antibody RRID:AB_10376183, Mouse Anti-TRA-1-81 RRID:AB_177638, RRID:AB_2118009, Rabbit Dach1 Polyclonal Antibody RRID:AB_2230330, RRID:AB_223647, RRID:AB_223651, Rabbit ZO-1 Polyclonal Antibody RRID:AB_2546345, Mouse purified anti-β-Amyloid RRID:AB_2564652, Total OXPHOS Rodent WB Antibody Cocktail RRID:AB_2629281, RRID:AB_2797642, Rabbit Monoclonal VGluT1 Antibody RRID:AB_2868428

Abstract

This study aims at implementing a 3D cell culture model of Alzheimer’s disease (AD). To that end we engineered human induced pluripotent stem cell (iPSC)-derived neural stem cells to conditionally overexpress FAD mutant APP and PSEN1 variants. After differentiation in 3D basement membrane matrices, cultures exhibited increased Aβ42 and Aβ40 levels and a highly pathogenic shift of the Aβ42/40 ratio. Typical AD phenotypes such as amyloid deposition and tau pathology were observed alongside impaired mitochondrial integrity and neuronal damage. Pathophenotypes were ameliorated by γ-secretase inhibition, confirming amyloid toxicity as main driver of AD pathology. iPSC-derived microglia added to the cultures engulfed Aβ and apoptotic cells, underscoring the modularity of this experimental system. We expect our model to provide a useful tool for assessing the impact of amyloid reduction on downstream AD pathologies such as mitochondrial dysfunction, neuroinflammation, and neurodegeneration, in particular in light of recent progress in the development and use of amyloid-targeting drugs.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

Tracing map

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Data

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Data and code availability

All data reported in this paper will be shared by the lead contact upon request.

This paper does not report original codes.

Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 6 keywords, 13 MeSH terms, 7 funders, 75 references, 11 RRIDs.

Cite

This paper

Hebisch, M., Kamin, V., Cenini, G., Piazzesi, A., Bertan, F., Weykopf, B., Schlee, J., Kaniyappan, S., Washicosky, K. J., Kim, D. Y., Bano, D., Peitz, M., & Brüstle, O. (2026). Recapitulation of plaque formation, tau pathology, and neurodegeneration in a human 3D matrix model of Alzheimer's disease. Cell reports methods, 6(4), 101365. https://doi.org/10.1016/j.crmeth.2026.101365

BibTeX

@article{hebisch2026recapitulation,
author = {Hebisch, Matthias and Kamin, Viola and Cenini, Giovanna and Piazzesi, Antonia and Bertan, Fabio and Weykopf, Beatrice and Schlee, Julia and Kaniyappan, Senthilvelrajan and Washicosky, Kevin J and Kim, Doo Yeon and Bano, Daniele and Peitz, Michael and Brüstle, Oliver},
title = {{Recapitulation of plaque formation, tau pathology, and neurodegeneration in a human 3D matrix model of Alzheimer's disease}},
journal = {Cell reports methods},
year = {2026},
month = mar,
volume = {6},
number = {4},
pages = {101365},
publisher = {Elsevier},
issn = {2667-2375},
doi = {10.1016/j.crmeth.2026.101365},
url = {https://doi.org/10.1016/j.crmeth.2026.101365},
pmid = {41916306},
pmcid = {PMC13106978}
}

RIS

TY - JOUR
AU - Hebisch, Matthias
AU - Kamin, Viola
AU - Cenini, Giovanna
AU - Piazzesi, Antonia
AU - Bertan, Fabio
AU - Weykopf, Beatrice
AU - Schlee, Julia
AU - Kaniyappan, Senthilvelrajan
AU - Washicosky, Kevin J
AU - Kim, Doo Yeon
AU - Bano, Daniele
AU - Peitz, Michael
AU - Brüstle, Oliver
TI - Recapitulation of plaque formation, tau pathology, and neurodegeneration in a human 3D matrix model of Alzheimer's disease
T2 - Cell reports methods
J2 - Cell Rep Methods
PY - 2026
DA - 2026/03/30
VL - 6
IS - 4
SP - 101365
SN - 2667-2375
PB - Elsevier
DO - 10.1016/j.crmeth.2026.101365
UR - https://doi.org/10.1016/j.crmeth.2026.101365
LA - en
ER -

CSL-JSON

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