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PreprintCited by 8Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAldose Reductase and Taurine

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Short-Chain Polyphosphates Induce Tau Fibrillation and Neurotoxicity in Human iPSC-Derived Retinal Neurons

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Baiocco, Paola, Barolo, Lorenzo, Mautone, Lorenza, Gigante, Ylenia, Ghirga, Silvia, Mura, Francesco, Farina, Maria Vittoria, Tacconi, Stefano, Dini, Luciana, Ruocco, Giancarlo, Boffi, Alberto, Milanetti, Edoardo, Angelantonio, Silvia Di·2024·Cell Death and Disease
DOI 10.21203/rs.3.rs-5409787/v1PMC PMC12064648

Preprint — published as 10.1038/s41419-025-07662-5

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Abstract

The onset of Alzheimer’s Disease and Frontotemporal Dementia is closely associated with the aggregation of tau, a multifunctional protein essential for neuronal stability and function. Given the role of tau aggregation in neurodegeneration, understanding the mechanisms behind its fibrils formation is crucial for developing therapeutic interventions to halt or reverse disease progression. However, the structural complexity and diverse aggregation pathways of tau present significant challenges, requiring comprehensive experimental studies. In this research, we demonstrate that short-chain polyphosphates, specifically sodium tripolyphosphate (NaTPP), effectively induce tau fibril formation in vitro using the microtubule-binding domain fragment (K18). NaTPP-induced fibrils display unique structural characteristics and aggregation kinetics compared to those induced by heparin, indicating distinct pathogenic pathways. Through molecular dynamics simulations, we show that NaTPP promotes aggregation by exposing key residues necessary for fibril formation, which remain concealed under non-aggregating conditions. This interaction drives tau into an aggregation-prone state, revealing a novel mechanism. Furthermore, our study indicates that human pluripotent stem cell-derived retinal neurons internalize NaTPP-induced fibrils within 24 hours, pointing to a potential pathway for tau spread in neurodegeneration. To explore the translational implications of NaTPP-induced fibrils, we assessed their long-term effects on cellular viability, tubulin integrity, and stress responses in retinal neuron cultures. Compared to heparin, NaTPP promoted fewer but longer fibrils with initially low cytotoxicity but induced a stress response marked by increased endogenous tau and p62/SQSTM1 expression. Prolonged exposure to NaTPP-induced oligomers significantly increased cytotoxicity, leading to tubulin fragmentation, altered caspase activity, and elevated levels of phosphorylated pathological tau. These findings align with a neurodegenerative phenotype, highlighting the relevance of polyphosphates in tau pathology. Overall, this research enhances our understanding of the role of polyphosphate in tau aggregation, linking it to key cellular pathways in neurodegeneration.

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Metadata

Authors
Baiocco, P., Barolo, L., Mautone, L., Gigante, Y., Ghirga, S., Mura, F., Farina, M. V., Tacconi, S., Dini, L., Ruocco, G., Boffi, A., Milanetti, E., & Angelantonio, S. D.
Affiliations
  • Italian Institute of Technology (IT)
  • Sapienza University of Rome (IT)
Corresponding author
  • Baiocco, Paola
  • Angelantonio, Silvia Di
ORCID
Venue
Cell Death and Disease
Publisher
Springer Science and Business Media LLC
Published
2024-12-02
Volume
16
Issue
1
Pages
369-369
ISSN
2041-4889 (ISSN-L)
DOI
10.21203/rs.3.rs-5409787/v1
PMC
PMC12064648
OpenAlex
W4410217890
Cited by
8
References
1
Citations by year
2026: 6 · 2025: 2
FWCI
5.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
Funders
  • Istituto Italiano di Tecnologia
  • Regione Lazio (A0375-2020-36549)
  • European Regional Development Fund (2014-2020’, A0375-2020-36549)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
Keywords
sodium tripolyphosphate, tau aggregation, retinal neurons, iPSC-derived neurons, neurotoxicity, heparin, tau oligomers, p62, caspase activation, Alzheimer's disease, frontotemporal dementia, molecular dynamics simulation
MeSH terms
Humans, Neurons, Polyphosphates, Retina, tau Proteins, Induced Pluripotent Stem Cells

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