RIPK1 expression and inhibition in tauopathies: implications for neuroinflammation and neuroprotection

Topic: Brain proteins, microglia and lab models

Tauopathies are a group of neurodegenerative diseases characterized by the alteration/aggregation of TAU protein. One of the main challenges of these diseases is that they have neither biomarkers nor pharmacological targets to stop the neurodegenerative process. Apart from the neurodegenerative process, tauopathies are also characterized by a chronic low-grade neuroinflammation process, where the receptor-interacting protein kinase 1 (RIPK1) protein plays an essential role. Our research aimed to explore the role of RIPK1 in various tauopathies. We examined mouse models of frontotemporal dementia (FTD), as well as brain tissue samples from patients with progressive supranuclear palsy (PSP), a primary form of 4R tauopathy, and Alzheimer’s disease (AD), which is considered a secondary tauopathy. Our findings show elevated levels of RIPK1 mRNA levels across various forms of tauopathies, in both mouse models and human tissue samples associated with primary and secondary TAU-related disorders. Furthermore, we investigated the potential of using a RIPK1 inhibitor, known as GSK2982772, in a mouse model as a novel treatment strategy for FTD. The data showed that GSK2982772 treatment effectively reduced the reactive astrocyte response triggered by TAUP301L overexpression. However, this RIPK1 inhibitor failed to protect against the neurodegeneration caused by elevated TAUP301L levels in the hippocampal region. These results suggest that although inhibiting RIPK1 activity may help reduce TAU-related astrogliosis in the brain, the complexity of the inflammatory pathways involved could explain the absence of neuroprotective effects against TAU-induced neurodegeneration.

Key findings

• Our findings show elevated levels of RIPK1 mRNA levels across various forms of tauopathies, in both mouse models and human tissue samples associated with primary and secondary TAU-related disorders.
• The data showed that GSK2982772 treatment effectively reduced the reactive astrocyte response triggered by TAUP301L overexpression.
• These results suggest that although inhibiting RIPK1 activity may help reduce TAU-related astrogliosis in the brain, the complexity of the inflammatory pathways involved could explain the absence of neuroprotective effects against TAU-induced neurodegeneration.

Why it matters

Levels of RIPK1 were elevated in mouse models and human tissue from several tau-related disorders, and a RIPK1 inhibitor reduced reactive astrocytes in a mouse model but did not protect against neurodegeneration. This suggests that blocking RIPK1 may reduce some inflammation but is not sufficient on its own to stop nerve cell loss.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.3389/fnins.2024.1530809
• PubMed: 39931431
• Original source →
• Free full text: Frontiers in Neuroscience →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{silvallanes2025-39931431,
  author  = {Silva-Llanes, Ignacio and Madruga, Enrique López and Martı́nez, Ana and Lastres‐Becker, Isabel},
  title   = {{RIPK1 expression and inhibition in tauopathies: implications for neuroinflammation and neuroprotection}},
  journal = {Frontiers in Neuroscience},
  year    = {2025},
  doi     = {10.3389/fnins.2024.1530809},
  pmid    = {39931431},
  url     = {https://doi.org/10.3389/fnins.2024.1530809}
}

Studies this one cites

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

• Neurodegenerative tauopathies Annual review of neuroscience · 2001-01-01 · usefulness score 54/100 · Lewy body dementia
• Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases Nature reviews. Neuroscience · 2019-01-01 · usefulness score 52/100 · Inflammation and the immune system
• Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly FEBS letters · 1998-10-01 · usefulness score 49/100 · Lewy body dementia

Related studies in Inflammation and the immune system

• TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease Journal of neuroinflammation · 2008-10-17 · usefulness score 40/100
• Human immunodeficiency virus type 1 infection alters chemokine beta peptide expression in human monocytes: implications for recruitment of leukocytes into brain and lymph nodes Proceedings of the National Academy of Sciences of the United States of America · 1996-01-01 · usefulness score 43/100
• Tau and neuroinflammation: What impact for Alzheimer's Disease and Tauopathies? Biomedical journal · 2018-02-01 · usefulness score 51/100
• Neuroinflammation and Tauopathies Molecular biology reports · 2026-06-30 · usefulness score 45/100
• Complement in the Brain: Contributions to Neuroprotection, Neuronal Plasticity, and Neuroinflammation Annual review of immunology · 2023-02-07 · usefulness score 41/100
• Alpha-synuclein stimulation of astrocytes: Potential role for neuroinflammation and neuroprotection Oxidative medicine and cellular longevity · 2010-07-01 · usefulness score 40/100

Also tagged “phosphorylated”

732 studies in the library carry the topic tag “phosphorylated”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 732 tagged studies.

• Modulatory effect of glial fibrillary acidic protein (GFAP) levels on the association between plasma p ‐tau217 levels and cognitive decline in older adults Alzheimer s & Dementia · 2025-12-01 · usefulness score 46/100 · Biomarkers
• Repeated plasma p‐tau217 measurements to monitor clinical progression heterogeneity Alzheimer s & Dementia · 2025-05-01 · usefulness score 63/100 · Mild cognitive impairment
• A mutation at codon 279 (N279K) in exon 10 of the Tau gene causes a tauopathy with dementia and supranuclear palsy Acta neuropathologica · 1999-07-01 · usefulness score 45/100 · Disease mechanisms

Similar studies

• TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging 2018 · Risk factors
• Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation 2001 · Inflammation and the immune system
• Tau and neuroinflammation in Alzheimer's disease: interplay mechanisms and clinical translation 2023 · Inflammation and the immune system
• Tau and tauopathies across primate species: implications for modeling neurodegenerative disorders 2025 · Disease mechanisms
• The role of tau in neurodegeneration 2009 · Lewy body dementia
• The importance of tau phosphorylation for neurodegenerative diseases 2013 · Lewy body dementia

More on Inflammation and the immune system

• A review that covers this ground Glial contributions to neurodegeneration in tauopathies Molecular neurodegeneration · 2017-06-29 · usefulness score 54/100
• Newest in this subject Molecular MRI of Neuroinflammation in Alzheimer's Disease using a Folate-targeted Nanoprobe bioRxiv · 2026-11-01 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject A Binding Site for CVN293 Reveals a Mechanism for Allosteric Control of THIK-1 K2P Channel Gating bioRxiv · 2026-10-28 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Inflammation and the immune system →