MAPT splicing modulators reduce 4R tau and rescue tauopathy phenotypes in human neurons and in a mouse model

Topic: Brain proteins, microglia and lab models

Tauopathies are neurodegenerative diseases characterized by the pathological accumulation of microtubule-associated protein tau (MAPT) in the brain. These disorders, like frontotemporal dementia (FTD-tau), currently lack effective therapies and can occur sporadically or be inherited when associated with MAPT gene mutations. Exon 10 and adjacent introns of the MAPT gene are a hotspot for pathogenic variants, including splicing mutations that enhance exon 10 inclusion and increase 4R tau expression and 4R-specific gain-of-function mutations that generate aggregation-prone tau. For these 4R tauopathies, a targeted messenger RNA (mRNA) splicing approach that promotes exon 10 exclusion may offer therapeutic benefit. We have developed splicing modulator compounds (SMCs) that promote MAPT exon 10 exclusion and demonstrated their efficacy in neurons derived from patients with FTD carrying the tau Pro 301 →Leu (P301L) gain-of-function mutation or the tau Ser 305 →Asn (S305N) splicing mutation. Treatment with SMC reduced 4R tau expression and decreased the accumulation of hyperphosphorylated tau (pTau) and oligomeric and insoluble tau proteoforms, thereby rescuing tau-associated neuronal toxicity. A lead SMC corrected the 3R/4R splice ratio in vivo and reduced pTau in the brain of a human gene-replacement mouse model expressing the tau Asn 279 →Lys (N279K) splicing mutation. These findings support the therapeutic potential of this class of small molecules and establish MAPT pre-mRNA splicing modulation as a promising strategy for the treatment of 4R tauopathies.

@article{silva2026-42616837,
  author  = {Silva, M. Catarina and Lindmeier, Hannah and Pigini, Paolo and Laughlin, J.S. and Yu, Yong and Morrill, Christie and Arnold, Michael A. and Barraza, Scott J. and others},
  title   = {{MAPT splicing modulators reduce 4R tau and rescue tauopathy phenotypes in human neurons and in a mouse model}},
  journal = {Science Translational Medicine},
  year    = {2026},
  doi     = {10.1126/scitranslmed.ady6759},
  pmid    = {42616837},
  url     = {https://doi.org/10.1126/scitranslmed.ady6759}
}

Key findings

• These disorders, like frontotemporal dementia (FTD-tau), currently lack effective therapies and can occur sporadically or be inherited when associated with MAPT gene mutations.
• We have developed splicing modulator compounds (SMCs) that promote MAPT exon 10 exclusion and demonstrated their efficacy in neurons derived from patients with FTD carrying the tau Pro 301 →Leu (P301L) gain-of-function mutation or the tau Ser 305 →Asn (S305N) splicing mutation.
• These findings support the therapeutic potential of this class of small molecules and establish MAPT pre-mRNA splicing modulation as a promising strategy for the treatment of 4R tauopathies.

Why it matters

Splicing modulator compounds reduced 4R tau and decreased hyperphosphorylated, oligomeric and insoluble tau in neurons from patients with frontotemporal dementia, and a lead compound corrected the 3R/4R splice ratio and reduced pTau in a mouse model. These findings support a possible therapeutic approach, but they come from cell and animal studies, not from testing in patients.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1126/scitranslmed.ady6759
• PubMed: 42616837
• Original source →

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Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17 Nature · 1998-06-01 · usefulness score 64/100 · Lewy body dementia
• Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging Neuropathology and applied neurobiology · 2015-02-01 · usefulness score 62/100 · Lewy body dementia
• Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling Neurology · 2021-06-22 · usefulness score 61/100 · Digital health tools
• Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17 Science (New York, N.Y.) · 1998-12-01 · usefulness score 59/100 · Lewy body dementia
• Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Aβ pathology are detected EMBO molecular medicine · 2020-11-10 · usefulness score 55/100 · Tau biomarkers
• Trans-cellular propagation of Tau aggregation by fibrillar species The Journal of biological chemistry · 2012-03-29 · usefulness score 51/100 · Lewy body dementia

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• Tangle-bearing neurons survive despite disruption of membrane integrity in a mouse model of tauopathy Journal of neuropathology and experimental neurology · 2009-07-01 · usefulness score 36/100
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• CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy Human molecular genetics · 2011-10-25 · usefulness score 36/100
• Cell-mediated neuroprotection in a mouse model of human tauopathy The Journal of neuroscience : the official journal of the Society for Neuroscience · 2010-07-01 · usefulness score 36/100
• Stimulation of autophagy is neuroprotective in a mouse model of human tauopathy Autophagy · 2012-08-09 · usefulness score 36/100

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