TY - JOUR
T1 - Altered ubiquitin signaling induces Alzheimer’s disease-like hallmarks in a three-dimensional human neural cell culture model
AU - Maniv, Inbal
AU - Sarji, Mahasen
AU - Bdarneh, Anwar
AU - Feldman, Alona
AU - Ankawa, Roi
AU - Koren, Elle
AU - Magid-Gold, Inbar
AU - Reis, Noa
AU - Soteriou, Despina
AU - Salomon-Zimri, Shiran
AU - Lavy, Tali
AU - Kesselman, Ellina
AU - Koifman, Naama
AU - Kurz, Thimo
AU - Kleifeld, Oded
AU - Michaelson, Daniel
AU - van Leeuwen, Fred W.
AU - Verheijen, Bert M.
AU - Fuchs, Yaron
AU - Glickman, Michael H.
N1 - Funding Information:
We would like to dedicate this article to our colleague Fred W. van Leeuwen who passed away during the preparation of the final version of the manuscript for publication, his visionary insight inspired us to continue the research project. We thank Rob A.I de Vos and the Laboratory for Pathology Eastern Netherlands, Hengelo, The Netherlands for procurement and Braak staging of brain samples from human donors, DY Kim for lentiviral vectors, N. Dantuma for an initial UBB construct, and P. Davies (Feinstein Institute for Medical Research, Manhasset, NY, USA) for his gift of MC1 and PHF-1 antibodies; Y. Yosefzon for discussion, advice, and technical assistance; E. Barak, S. Kirzner, R. Lerer, and N. Dahan for assistance with FACS and microscopy; T. Ziv and members of the THHI Proteomics facility for mass spectrometry. We aknowledge funding from ICRF acceleration and Israel Science Foundation grants (YF), Schmidt Futures and The Israel Science Foundation (755/19) (MHG), and BIRAX and Alzheimer Society (73BX16TKMG) (TK and MHG). +1
Funding Information:
We would like to dedicate this article to our colleague Fred W. van Leeuwen who passed away during the preparation of the final version of the manuscript for publication, his visionary insight inspired us to continue the research project. We thank Rob A.I de Vos and the Laboratory for Pathology Eastern Netherlands, Hengelo, The Netherlands for procurement and Braak staging of brain samples from human donors, DY Kim for lentiviral vectors, N. Dantuma for an initial UBB+1construct, and P. Davies (Feinstein Institute for Medical Research, Manhasset, NY, USA) for his gift of MC1 and PHF-1 antibodies; Y. Yosefzon for discussion, advice, and technical assistance; E. Barak, S. Kirzner, R. Lerer, and N. Dahan for assistance with FACS and microscopy; T. Ziv and members of the THHI Proteomics facility for mass spectrometry. We aknowledge funding from ICRF acceleration and Israel Science Foundation grants (YF), Schmidt Futures and The Israel Science Foundation (755/19) (MHG), and BIRAX and Alzheimer Society (73BX16TKMG) (TK and MHG).
Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Alzheimer’s disease (AD) is characterized by toxic protein accumulation in the brain. Ubiquitination is essential for protein clearance in cells, making altered ubiquitin signaling crucial in AD development. A defective variant, ubiquitin B + 1 (UBB+1), created by a non-hereditary RNA frameshift mutation, is found in all AD patient brains post-mortem. We now detect UBB+1 in human brains during early AD stages. Our study employs a 3D neural culture platform derived from human neural progenitors, demonstrating that UBB+1 alone induces extracellular amyloid-ß (Aß) deposits and insoluble hyperphosphorylated tau aggregates. UBB+1 competes with ubiquitin for binding to the deubiquitinating enzyme UCHL1, leading to elevated levels of amyloid precursor protein (APP), secreted Aß peptides, and Aß build-up. Crucially, silencing UBB+1 expression impedes the emergence of AD hallmarks in this model system. Our findings highlight the significance of ubiquitin signalling as a variable contributing to AD pathology and present a nonclinical platform for testing potential therapeutics.
AB - Alzheimer’s disease (AD) is characterized by toxic protein accumulation in the brain. Ubiquitination is essential for protein clearance in cells, making altered ubiquitin signaling crucial in AD development. A defective variant, ubiquitin B + 1 (UBB+1), created by a non-hereditary RNA frameshift mutation, is found in all AD patient brains post-mortem. We now detect UBB+1 in human brains during early AD stages. Our study employs a 3D neural culture platform derived from human neural progenitors, demonstrating that UBB+1 alone induces extracellular amyloid-ß (Aß) deposits and insoluble hyperphosphorylated tau aggregates. UBB+1 competes with ubiquitin for binding to the deubiquitinating enzyme UCHL1, leading to elevated levels of amyloid precursor protein (APP), secreted Aß peptides, and Aß build-up. Crucially, silencing UBB+1 expression impedes the emergence of AD hallmarks in this model system. Our findings highlight the significance of ubiquitin signalling as a variable contributing to AD pathology and present a nonclinical platform for testing potential therapeutics.
U2 - 10.1038/s41467-023-41545-7
DO - 10.1038/s41467-023-41545-7
M3 - Article
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5922
ER -