OSCR

FKBP51 inhibition by SAFit2 modulates tau pathology and cognitive deficits in PS19 mice.

Overview

Authors: Andrea Contreras-Marciales1,2, Daniela Mezquite-Garcia1,2, Laura A Verdina1,2, Ahmed Elnahrawy3, Tiara Wolf4, Jennifer Guergues4, Priyanshi Parikh1,2, Elle R Hunter1,2, Diana Hernandez Acosta1,2, Stanley M Stevens Jr4, Shannon E Hill1,2,3, Laura J Blair1,2,5
ORCID iDs: Shannon E Hill, Laura J Blair
  1. Byrd Alzheimer’s Center and Research Institute, 4001 E. Fletcher Ave, Tampa, FL 33613 USA
  2. Department of Molecular Medicine, University of South Florida, 4202 E. Fowler Ave, Tampa, FL USA
  3. Department of Chemistry, University of South Florida, 4202 E. Fowler Ave, Tampa, FL USA
  4. Department of Molecular Biosciences, University of South Florida, 4202 E. Fowler Ave, Tampa, FL USA
  5. Research & Development, James A. Haley Veterans’ Hospital, 13000 Bruce B. Downs Blvd, Tampa, FL USA
Institutions: University of South Florida (United States); USF Health Byrd Alzheimer's Institute (United States); James A. Haley Veterans' Hospital (United States)
Journal: Alzheimer's research & therapy, volume 18, issue 1, article 183
Dates: received 20 December 2025; accepted 1 June 2026; published online 6 June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s13195-026-02107-3 · PMID 42251444 · PMCID PMC13463937 · OpenAlex W7163736279
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), human (organism), mouse (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics, fMRI & imaging
Keywords: Tau, FK506-binding protein, Transgenic mice, Mass spectrometry, SAFit2, FKBP51
MeSH: Cognitive Dysfunction*, Tacrolimus Binding Proteins*, tau Proteins*, Tauopathies*, Animals, Brain, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Transgenic, Morpholines, Piperidines, Tacrolimus Binding Protein 5 (* major topic)
Topic: Alzheimer's disease research and treatments (Physiology, Medicine), according to OpenAlex
Funding: National Institute on Aging (R01 NS073899); U.S. Department of Veterans Affairs (I01 BX004626); NINDS NIH HHS (R01 NS073899); Alzheimer’s Association (AARG-22-974562); National Institute of Neurological Disorders and Stroke (R01 NS073899); Alzheimer's Association (AARG-22-974562); BLRD VA (I01 BX004626); NIA NIH HHS (R01 NS073899)
Citations: not cited yet (Europe PMC); 88 references in the paper
Research resources: Actin RRID:AB_10700003, GFAP RRID:AB_10917109, Anti-rabbit RRID:AB_143165, FKBP51 RRID:AB_2103136, Tau pSer202 + Thr205 RRID:AB_223648, Goat anti-Rabbit IgG Alexa Fluor™ 594 RRID:AB_2534095, Anti-chicken RRID:AB_2534099, Goat anti-Rabbit IgG Alexa Fluor™ 647 RRID:AB_2535813, Tau Polyclonal Antibody RRID:AB_2544763, Total Tau RRID:AB_2721194, Anti-goat RRID:AB_2762828, Tau pThr231 RRID:AB_2771607, Oligomeric Tau RRID:AB_3608345, Iba-1 RRID:AB_839504

Abstract

The accumulation of pathogenic tau protein is linked to cognitive decline and neuronal loss in Alzheimer’s disease (AD), with tau oligomers identified as particularly neurotoxic. The 51 kDa FK506-binding protein (FKBP51) stabilizes these toxic tau oligomers and has been identified as a risk factor for several neurodegenerative diseases. FKBP51 levels increase with age and are especially high in AD brains, suggesting its involvement in disease progression. The development of the selective FKBP51 inhibitor, SAFit2, which can cross the blood-brain barrier, has shown promise in reducing stress hormones, improving stress responses, and mitigating protein-related pathologies in other neurodegenerative models. However, the effects of SAFit2 on tauopathies, such as those seen in AD, have not yet been investigated. Here, the effects of the FKBP51-selective inhibitor, SAFit2, were evaluated in PS19 tau transgenic mice. Mice received a 28-day regimen of SAFit2, followed by comprehensive behavioral, neuropathological, and proteomic analyses. SAFit2 demonstrated effective brain penetrance, with sex-dependent pharmacokinetics. Treatment slowed cognitive decline and depressive-like behavior, with pronounced benefits in male PS19 mice, including improved spatial memory and reduced tau oligomer burden. In females, SAFit2 promoted clearance of AT8-positive tau multimers with some benefit to recognition memory. Proteomic profiling revealed distinct molecular signatures underlying these sex-specific responses: males exhibited upregulation of RNA processing and ribosomal proteins, while females showed restoration of calcium signaling and synaptic drivers. Notably, behavioral recovery occurred independently of widespread neuroinflammation reversal. These findings provide the first in vivo evidence that FKBP51 inhibition by SAFit2 induces sex-specific remodeling of the brain proteome. This study also provides further evidence for the therapeutic benefits of targeting FKBP51 for tauopathies.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13195-026-02107-3.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

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Data

Datasets cited

Data availability

Data is provided within the manuscript or supplementary information files. The mass spectrometric data were deposited to Mass Spectrometry Interactive Virtual Environment (MassIVE), which is part of the ProteomeXchange Consortium, with the dataset identifier MSV000100258.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 6 keywords, 15 MeSH terms, 8 funders, 87 references, 14 RRIDs.

Cite

This paper

Contreras-Marciales, A., Mezquite-Garcia, D., Verdina, L. A., Elnahrawy, A., Wolf, T., Guergues, J., Parikh, P., Hunter, E. R., Hernandez Acosta, D., Stevens, S. M., Hill, S. E., & Blair, L. J. (2026). FKBP51 inhibition by SAFit2 modulates tau pathology and cognitive deficits in PS19 mice. Alzheimer's research & therapy, 18(1), 183. https://doi.org/10.1186/s13195-026-02107-3

BibTeX

@article{contrerasmarciales2026fkbp51,
author = {Contreras-Marciales, Andrea and Mezquite-Garcia, Daniela and Verdina, Laura A and Elnahrawy, Ahmed and Wolf, Tiara and Guergues, Jennifer and Parikh, Priyanshi and Hunter, Elle R and Hernandez Acosta, Diana and Stevens, Stanley M and Hill, Shannon E and Blair, Laura J},
title = {{FKBP51 inhibition by SAFit2 modulates tau pathology and cognitive deficits in PS19 mice}},
journal = {Alzheimer's research \& therapy},
year = {2026},
month = jun,
volume = {18},
number = {1},
pages = {183},
publisher = {BMC},
issn = {1758-9193},
doi = {10.1186/s13195-026-02107-3},
url = {https://doi.org/10.1186/s13195-026-02107-3},
pmid = {42251444},
pmcid = {PMC13463937}
}

RIS

TY - JOUR
AU - Contreras-Marciales, Andrea
AU - Mezquite-Garcia, Daniela
AU - Verdina, Laura A
AU - Elnahrawy, Ahmed
AU - Wolf, Tiara
AU - Guergues, Jennifer
AU - Parikh, Priyanshi
AU - Hunter, Elle R
AU - Hernandez Acosta, Diana
AU - Stevens, Stanley M
AU - Hill, Shannon E
AU - Blair, Laura J
TI - FKBP51 inhibition by SAFit2 modulates tau pathology and cognitive deficits in PS19 mice
T2 - Alzheimer's research & therapy
J2 - Alzheimers Res Ther
PY - 2026
DA - 2026/06/06
VL - 18
IS - 1
SP - 183
SN - 1758-9193
PB - BMC
DO - 10.1186/s13195-026-02107-3
UR - https://doi.org/10.1186/s13195-026-02107-3
LA - en
ER -

CSL-JSON

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