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Impairment of neuronal activity occurs at the early stages of the aggregation cascade of Aβ1-42 and mutant Tau.

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Title: Impairment of neuronal activity occurs at the early stages of the aggregation cascade of Aβ1-42 and mutant Tau.
Authors: Hirsch F; Department of Cell Biology, University of Bremen, Leobener Strasse 2, 28359 Bremen, Germany., F Läubli N; Molecular Neuroscience Group, Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa-Fawcett Drive, Cambridge CB3 0AS, UK., Kelkar A; Leibniz Institute on Aging - Fritz-Lipmann-Institute, Beutenbergstrasse 11, 07745 Jena, Germany., Sleiman M; Leibniz Institute on Aging - Fritz-Lipmann-Institute, Beutenbergstrasse 11, 07745 Jena, Germany., Woitzat Y; Leibniz Institute on Aging - Fritz-Lipmann-Institute, Beutenbergstrasse 11, 07745 Jena, Germany., Gallrein C; Leibniz Institute on Aging - Fritz-Lipmann-Institute, Beutenbergstrasse 11, 07745 Jena, Germany., Gumz V; Leibniz Institute on Aging - Fritz-Lipmann-Institute, Beutenbergstrasse 11, 07745 Jena, Germany., Kalsi GK; Leibniz Institute on Aging - Fritz-Lipmann-Institute, Beutenbergstrasse 11, 07745 Jena, Germany., Fernandez-Villegas A; Molecular Neuroscience Group, Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa-Fawcett Drive, Cambridge CB3 0AS, UK., Schierle GSK; Molecular Neuroscience Group, Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa-Fawcett Drive, Cambridge CB3 0AS, UK., Kirstein J; Leibniz Institute on Aging - Fritz-Lipmann-Institute, Beutenbergstrasse 11, 07745 Jena, Germany.; Friedrich-Schiller-Universität, Institute for Biochemistry & Biophysics, Hans Knöll-Strasse 2, 07745 Jena, Germany.
Source: Disease models & mechanisms [Dis Model Mech] 2026 Mar 01; Vol. 19 (3). Date of Electronic Publication: 2026 Apr 01.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Company of Biologists Ltd Country of Publication: England NLM ID: 101483332 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1754-8411 (Electronic) Linking ISSN: 17548403 NLM ISO Abbreviation: Dis Model Mech Subsets: MEDLINE
Imprint Name(s): Original Publication: Cambridge : Company of Biologists Ltd., c2008-
MeSH Terms: Amyloid beta-Peptides*/metabolism , tau Proteins*/metabolism , tau Proteins*/genetics , Neurons*/metabolism , Neurons*/pathology , Mutation*/genetics , Peptide Fragments*/metabolism , Mutant Proteins*/metabolism , Protein Aggregates* , Protein Aggregation, Pathological*, Caenorhabditis elegans/metabolism ; Aging/pathology ; Aging/metabolism ; Muscles/metabolism ; Muscles/pathology ; Calcium/metabolism ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Animals ; Proteotoxic Stress
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary Tau tangles, ultimately leading to brain atrophy and death. To elucidate the relationship between the aberrant folding and aggregation of Aβ and mutant Tau and neuronal function, we monitored neuronal activity in C. elegans AD models across age. For that, we used a neuronal GCaMP reporter to monitor fluctuations in Ca2+ and developed microfluidic devices to immobilize nematodes to non-invasively assess neuronal activity. Our findings revealed that expression of both Aβ and Tau lead to significant reductions in neuronal activity and function in young adult animals, preceding the accumulation of amyloid aggregates. Notably, Aβ expression and aggregation in muscle tissue produced detrimental effects on neuronal activity comparable to those seen after expression in neurons, suggesting that proteotoxic stress in muscle can influence neuronal function. This may occur through propagation of Aβ from muscle to neurons or through retrograde signaling pathways. Further, our new sub-stoichiometrically labeled Tau strains highlight the significant impact TauP301L,V337M has on neuronal activity throughout aging. These results enhance our understanding of the early functional effects of amyloid aggregation in Alzheimer's disease.
(© 2026. Published by The Company of Biologists.)
Competing Interests: Competing interests The authors declare no competing or financial interests.
Comments: Update of: bioRxiv. 2025 Jul 24:2025.07.21.665894. doi: 10.1101/2025.07.21.665894.. (PMID: 40777286)
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Grant Information: KI1988/7-1 Deutsche Forschungsgemeinschaft; MR/K02292X/1 United Kingdom MRF_ MRF_; ARUK-PG013-14 Alzheimer's Research UK; 20052CB Alzheimer Forschung Initiative; Universität Bremen; KI1988/7-1 Deutsche Forschungsgemeinschaft (DFG); 065807/Z/01/Z United Kingdom WT_ Wellcome Trust; 203249/Z/16/Z United Kingdom WT_ Wellcome Trust; MR/K02292X/1 Medical Research Council (MRC); ARUK-PG013-14 Alzheimer Research UK (ARUK); 16238 Michael J. Fox Foundation
Contributed Indexing: Keywords: C. elegans; Abeta; Aging; Alzheimers disease; Neurodegeneration; Tau
Substance Nomenclature: 0 (Amyloid beta-Peptides)
0 (tau Proteins)
0 (amyloid beta-protein (1-42))
0 (Peptide Fragments)
0 (Protein Aggregates)
0 (Mutant Proteins)
SY7Q814VUP (Calcium)
Entry Date(s): Date Created: 20260223 Date Completed: 20260708 Latest Revision: 20260813
Update Code: 20260813
PubMed Central ID: PMC13072132
DOI: 10.1242/dmm.052295
PMID: 41725344
Database: MEDLINE
Description
ISSN:1754-8411
DOI:10.1242/dmm.052295