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Passive immunization against phosphorylated tau improves features of Huntington's disease pathology

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Alpaugh, Melanie, Masnata, Maria, de Rus Jacquet, Aurelie, Lepinay, Eva, Denis, Hélèna L., Saint-Pierre, Martine, Davies, Peter, Planel, Emmanuel +1 more·2022·Molecular Therapy
DOI 10.1016/j.ymthe.2022.01.020PMC PMC9077324
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Abstract

Huntington's disease is classically described as a neurodegenerative disorder of monogenic aetiology. The disease is characterized by an abnormal polyglutamine expansion in the huntingtin gene, which drives the toxicity of the mutated form of the protein. However, accumulation of the microtubule-associated protein tau, which is involved in a number of neurological disorders, has also been observed in patients with Huntington's disease. In order to unravel the contribution of tau hyperphosphorylation to hallmark features of Huntington's disease, we administered weekly intraperitoneal injections of the anti-tau pS202 CP13 monoclonal antibody to zQ175 mice and characterized the resulting behavioral and biochemical changes. After 12 weeks of treatment, motor impairments, cognitive performance and general health were improved in zQ175 mice along with a significant reduction in hippocampal pS202 tau levels. Despite the lack of effect of CP13 on neuronal markers associated with Huntington's disease pathology, tau-targeting enzymes and gliosis, CP13 was shown to directly impact mutant huntingtin aggregation such that brain levels of amyloid fibrils and huntingtin oligomers were decreased, while larger huntingtin protein aggregates were increased. Investigation of CP13 treatment of Huntington's disease patient-derived induced pluripotent stem cells (iPSCs) revealed a reduction in pS202 levels in differentiated cortical neurons and a rescue of neurite length. Collectively, these findings suggest that attenuating tau pathology could mitigate behavioral and molecular hallmarks associated with Huntington's disease.

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  • In HD models, tau ablation reduces motor abnormalities and restores neurite length.

    “while in HD models, ablation led to reduced motor abnormalities and restoration of neurite length [83, 84].”

    From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [83]

    The Results report reduced motor impairment in CP13-treated HD mice, and the Discussion reports that CP13 rescued neurite retraction in HD-derived neurons. But CP13 is an antibody treatment, not tau ablation. The Discussion separately describes improved motor features after reduced Mapt expression in an earlier study; it does not link ablation to the neurite-length result. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Alpaugh, M., Masnata, M., de Rus Jacquet, A., Lepinay, E., Denis, H. L., Saint-Pierre, M., Davies, P., Planel, E., & Cicchetti, F.
Affiliations
  • Université Laval (CA)
  • Albert Einstein College of Medicine (US)
Corresponding author
Cicchetti, Francesca
ORCID
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2022-04
Volume
30
Issue
4
Pages
1500-1522
ISSN
1525-0016 (ISSN-L)
DOI
10.1016/j.ymthe.2022.01.020
PMC
PMC9077324
OpenAlex
W4205239057
Cited by
25
References
17
Citations by year
2026: 3 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 3
FWCI
2.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Canadian Institutes of Health Research
  • Fonds de recherche du Quebec Sante
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
Huntington's disease, tau hyperphosphorylation, passive immunization, zQ175 mice, mutant huntingtin aggregation, amyloid fibrils, motor impairment, cognitive impairment, iPSC-derived cortical neurons, neurite length, gliosis
MeSH terms
Huntingtin Protein, Animals, Brain, Disease Models, Animal, Humans, Huntington Disease, Immunization, Passive, Neurons, Mice, Induced Pluripotent Stem Cells

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