Cited by 488Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Monoclonal antibody PHF‐1 recognizes tau protein phosphorylated at serine residues 396 and 404

Otvos, L., Feiner, L., Lang, E., Szendrei, G. I., Goedert, M., Lee, V. M‐Y.·1994·Journal of Neuroscience Research

DOI 10.1002/jnr.490390607

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Abstract

The microtubule‐associated protein τ is hyperphosphorylated in the paired helical filaments (PHFs) of Alzheimer's disease. Immunological and direct chemical studies have identified Ser 396 and Ser 404 as two of the phosphorylated sites. Previously, we have demonstrated, using synthetic τ peptides containing phosphorylated Ser 396 , that this site is recognized by the monoclonal antibody PHF‐1. The present sudy extends this observation by showing that PHF‐1 recognizes τ peptides containing either individually phosphorylated Ser 396 or Ser 404 , but that there is a >10‐fold increase in the sensitivity of detection of τ peptides by PHF‐1 when both serines are phosphorylated. The recognition of singly or doubly phosphorylated Ser 396 and Ser 404 in τ by PHF‐1 can also be demonstrated in Chinese hamster ovary cells transfected with full‐length wild‐type τ constructs or mutant constructs with Ala substituted for Ser 396 or Ser 404 . We conclude that the PHF‐1 epitope contains both phosphorylated Ser 396 and Ser 404 . © 1994 Wiley‐Liss, Inc.

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Bai, Q., Shao, E., Ma, D., Jiao, B., Scheetz, S. D., Hartnett, K. A., Ильин, В. Н., Aizenman, E., Kofler, J., & Burton, E. A. (2024) · Nature Communications · doi:10.1038/s41467-024-52173-0 · Cited by 16
Dose-dependent phosphorylation of endogenous Tau by intermittent hypoxia in rat brain
Marciante, A. B., Howard, J. C., Kelly, M. N., Santiago‐Moreno, J., Allen, L. L., Gonzalez‐Rothi, E. J., & Mitchell, G. S. (2022) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00332.2022 · Cited by 15
SPOP loss of function protects against tauopathy
Eck, R. J., Kow, R. L., Black, A. H., Liachko, N. F., & Kraemer, B. C. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2207250120 · Cited by 16
“S11 and S12) (29, 30).”
4,4-Difluoroproline as a Unique 19 F NMR Probe of Proline Conformation
Ganguly, H. K., Ludwig, B. A., Tressler, C. M., Bhatt, M. R., Pandey, A. K., Quinn, C. M., Bai, S., Yap, G. P. A., & Zondlo, N. J. (2024) · Biochemistry · doi:10.1021/acs.biochem.3c00697 · Cited by 14
Genetic ablation of tau in postnatal neurons rescues decreased adult hippocampal neurogenesis in a tauopathy model
Houben, S., Leroy, K., Ando, K., Yilmaz, Z., Widomski, C., Buée, L., & Brion, J. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.02.021 · Cited by 16
Social interaction attenuates the extent of secondary neuronal damage following closed head injury in mice
Doulames, V. M., Vilcans, M., Lee, S., & Shea, T. B. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00275 · Cited by 16
“We therefore derived a ratio of PHF-1-reactive tau vs. total tau (as visualized by antibody Tau-5, which reacts with tau regardless of phosphorylation state).”
BackgroundInfluential
14-3-3ζ does not increase GSK3β-mediated tau phosphorylation in cell culture models
Matthews, T. A., & Johnson, G. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.04.101 · Cited by 15
Early but not late conformational changes of tau in association with ubiquitination of neurofibrillary pathology in Alzheimer’s disease brains
Ibarra-Bracamontes, V., Escobar‐Herrera, J., Krištofíková, Z., Řı́pová, D., Florán, B., & García‐Sierra, F. (2020) · Brain Research · doi:10.1016/j.brainres.2020.146953 · Cited by 14
Development of an Assay to Screen for Inhibitors of Tau Phosphorylation by Cdk5
Ahn, J. S., Musacchio, A., Mapelli, M., Ni, J., Scinto, L. F. M., Stein, R. L., Kosik, K. S., & Yeh, L.-A. (2004) · SLAS DISCOVERY · doi:10.1177/1087057103260594 · Cited by 13
“PHF-1 is a monoclonal antibody(24) directed against the phosphorylated tau epitope formed by serine 396 and serine 404.(8,25) Mutation studies with human tau indicate that phosphorylation by cdk5 at serine 396 and serine 404 is primarily responsible for the functional loss of tau-mediated tubulin polymerization.”
Background
Multiple Forms of Phosphatase from Human Brain: Isolation and Partial Characterization of Affi-Gel Blue Binding Phosphatases
Cheng, L. Y., Wang, J., Gong, C., Pei, J.-J., Zaidi, T., Grundke, I., & Iqbal, K. (2000) · Neurochemical Research · doi:10.1023/a:1007547701518 · Cited by 14
Gliosis Precedes Amyloid-β Deposition and Pathological Tau Accumulation in the Neuronal Cell Cycle Re-Entry Mouse Model of Alzheimer’s Disease
Park, K. H. J., & Barrett, T. (2020) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-200170 · Cited by 12
“PHF-1 antibody labels pSer396/404 tau, which is associated with paired helical filaments in AD [36].”
Background
Simple, Single-Shot Phosphoproteomic Analysis of Heat-Stable Tau Identifies Age-Related Changes in pS235- and pS396-Tau Levels in Non-human Primates
Leslie, S. N., Kanyo, J. E., Datta, D., Wilson, R. S., Zeiss, C. J., Duque, A., Lam, T. T., Arnsten, A. F. T., & Nairn, A. C. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.767322 · Cited by 14
“Phosphorylation at both of these sites has been previously associated with human AD tau pathology (Otvos et al., 1994; Kimura et al., 1996; Brici et al., 2018).”
Background
Tau modifiers as therapeutic targets for Alzheimer's disease
Liu, Q., Lee, H., Honda, K., Siedlak, S. L., Harris, P. L. R., Cash, A., Zhu, X., Ávila, J., Nunomura, A., Takeda, A., et al. (2004) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2004.06.021 · Cited by 14
Histopathologic changes induced by the microtubule‐stabilizing agent Taxol in the rat hippocampus in vivo
Mercado-Gómez, O. F., Ferrera, P., & Arias, C. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20264 · Cited by 12
Tau Protein: Function and Pathology
Rosenmann, H., Blum, D. L., Kayed, R., & Ittner, L. M. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/707482 · Cited by 12
Temperature-induced Artifacts in Tau Phosphorylation: Implications for Reliable Alzheimer’s Disease Research
Canet, G., Rocaboy, E., Laliberté, F., Boscher, E., Guisle, I., Diego-Diàz, S., Fereydouni-Forouzandeh, P., Whittington, R. A., Hébert, S. S., Pernet, V., et al. (2023) · Experimental Neurobiology · doi:10.5607/en23025 · Cited by 12
“…level was assessed using specific antibodies targeting phosphorylated tau at distinct epitopes, including AT270 (pThr181) [23], pSer199, CP13 (pSer202) [24], pThr205, AT100 (pThr212/pSer214) [25], MC6 (pSer235) [26], pSer262, PHF1 (pSer396/pSer404) [27], pSer409, and pSer422 (Table 1).”
O-GlcNAc modification differentially regulates microtubule binding and pathological conformations of tau isoforms in vitro
Alhadidy, M. M., Stemmer, P. M., & Kanaan, N. M. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.108263 · Cited by 13
“On the C-terminus of tau, phosphorylation at S422 and the paired helical ﬁ lament-1 epitope (S396/S404) is upregulated early in several tauopathies (11, 78 – 83).”
The olfactory epithelium: a critical gateway for pathological tau propagation and a target for mitigating tauopathy in the central nervous system
Dourte, M., Paître, E., Bouchoucha, M., Boyer, E., Tomé, S. O., Doeraene, E., Huart, C., Leroy, K., Thal, D. R., Decottignies, A., et al. (2025) · Acta Neuropathologica · doi:10.1007/s00401-025-02902-6 · Cited by 12
“It binds to tau filaments and is a recognized standard to evidence the pathological conformations found in NFTs [30, 50].”
Connectivity as a universal predictor of tau progression in atypical Alzheimer’s disease
de Bruin, H., Groot, C., Barthel, H., Bischof, G. N., Blazhenets, G., Boellaard, R., Boon, B. D. C., Brendel, M., Cash, D. M., Coath, W., et al. (2025) · Brain · doi:10.1093/brain/awaf279 · Cited by 13
Retinal tau phosphorylation in Alzheimer's disease: A mass spectrometry study
Santiago, J., Pocevičiūtė, D., Vogel, J. W., Bank, T. N. B., Brinkmalm, G., & Wennström, M. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.107057 · Cited by 10
Behavioral and neuropathological characterization over the adult lifespan of the human tau knock-in mouse
Benskey, M. J., Panoushek, S., Saito, T., Saido, T. C., Grabinski, T. M., & Kanaan, N. M. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1265151 · Cited by 13
“The PHF1 antibody was originally developed to immunolabel tau protein in paired helical filaments (Greenberg et al., 1992; Otvos et al., 1994).”
Method
Plant-based vaccines for Alzheimer's disease: an overview
Rosales‐Mendoza, S., Rubio‐Infante, N., Zarazúa, S., Govea‐Alonso, D. O., Martel‐Gallegos, G., & Moreno‐Fierros, L. (2014) · Expert Review of Vaccines · doi:10.1586/14760584.2014.874948 · Cited by 11
“The PHF1 monoclonal antibody, which recognizes an epitope encompassing p-Ser396, 404 [79], was tested in mice immunized by the intraperitoneal route that reduced tau pathology [74].”
Method
Structural characterization of monoclonal antibodies targeting C-terminal Ser404 region of phosphorylated tau protein
Chukwu, J. E., Congdon, E. E., Sigurdsson, E. M., & Kong, X. (2019) · mAbs · doi:10.1080/19420862.2019.1574530 · Cited by 12
Neuronal Cell Cycle Re-Entry Enhances Neuropathological Features in App NLF Knock-In Mice
Barrett, T., Stangis, K. A., Saito, T., Saido, T. C., & Park, K. H. J. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210091 · Cited by 12
Effect of cortistatin on tau phosphorylation at Ser262 site
Rubio, A., Pérez, M., de Lecea, L., & Ávila, J. (2008) · Journal of Neuroscience Research · doi:10.1002/jnr.21689 · Cited by 11
Alzheimer PHF-tau aggregates do not spread tau pathology to the brain via the Retino-tectal projection after intraocular injection in male mouse models
de Fisenne, M.-A., Yilmaz, Z., Decker, R. D., Suain, V., Buée, L., Ando, K., Brion, J., & Leroy, K. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105875 · Cited by 10
A mouse model to study tau pathology related with tau phosphorylation and assembly
Engel, T., Lucas, J. J., Hernández, F., & Ávila, J. (2007) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2007.01.047 · Cited by 10
The toxin MPTP generates similar cognitive and locomotor deficits in hTau and tau knock-out mice
Gratuze, M., Josset, N., Petry, F. R., Pflieger, M., Jong, L. E., Truchetti, G., Poitras, I., Julien, J., Bezeau, F., Morin, F., et al. (2019) · Brain Research · doi:10.1016/j.brainres.2019.01.016 · Cited by 10
A 4R tauopathy develops without amyloid deposits in aged cat brains
Poncelet, L., Ando, K., Vergara, C., Mansour, S., Suain, V., Yilmaz, Z., Reygel, A., Gilissen, E., Brion, J., & Leroy, K. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.05.024 · Cited by 10
Binding specificity of monoclonal antibody AD2: influence of the phosphorylation state of tau
Torreilles, F., Roquet, F., Granier, C., Pau, B., & Mourton-Gilles, C. (2000) · Molecular Brain Research · doi:10.1016/s0169-328x(00)00073-5 · Cited by 10
Type I Interferon Signaling Drives Microglial Dysfunction and Senescence in Human iPSC Models of Down Syndrome and Alzheimer's DiseasePreprint
Jin, M., Xu, R., Alam, M. M., Ma, Z., Zhu, S., Wang, L., Martini, A. C., Bernabucci, M., Xie, P., Kwan, K. Y., et al. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3985173 · Cited by 10
GSK3β phosphorylation catalyzes the aggregation of Tau into Alzheimer’s disease-like amyloid strainPreprint
Chakraborty, P., de Opakua, A. I., Purslow, J. A., Fromm, S. A., Chatterjee, D., Zachrdla, M., Puri, S., Wolozin, B. L., & Zweckstetter, M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.12.19.572292 · Cited by 10
“The above experiments show that the specific phosphorylation of the PHF-1 epitope by GSK3 b promotes the condensation of tau into gel-like structures that further convert into amyloid fibrils under conditions of agitation.”
BackgroundInfluential
Tau-mediated axonal degeneration is prevented by activation of the WldS pathway
Stubbs, K., Batchelor, B. G., Sivanantharajah, L., Sealey, M. A., Moreno, M. R., Ruiz, E., Richardson, B., Perry, V. H., Newman, T. A., & Mudher, A. K. (2023) · Brain Communications · doi:10.1093/braincomms/fcad052 · Cited by 9
“To investigate this, hTau phosphorylated at the ser396/404 site (detected by the PHF-1 antibody 57 ) was quantified in 6-week hTau 0N3R ;Wld S axons with and without Wld S pathway activation.”
Cerebral Aβ deposition in an Aβ-precursor protein-transgenic rhesus monkey
Chan, A. W. S., Cho, I. K., Li, C., Zhang, X., Patel, S., Rusnak, R., Raper, J., Bachevalier, J., Moran, S. P., Chi, T., et al. (2022) · Aging Brain · doi:10.1016/j.nbas.2022.100044 · Cited by 10
“Davies (Antibody Registry AB_2315150), raised against detergent-extracted PHF preparations, with an epitope around phosphoserine 396/404 [51], anti-glial fibrillary acidic protein (GFAP) (1:5000) purified immunoglobulin fraction of rabbit anti-serum from Dako (Carpinteria, CA; Antibody Registry AB_10013382), raised ag…”
Mechanisms of increased Alzheimer’s disease pathology with R47H and R62H TREM2 variants
Fancy, N. N., Willumsen, N., Chau, V. M. N., Boulger, S. L., Whitwell, H. J., Wang, W., Avot, B., Thomas, M., Talbot-Martin, J., Tsartsalis, S., et al. (2026) · Acta Neuropathologica · doi:10.1007/s00401-026-03036-z · Cited by 8
Molecular Dynamics Simulation of Tau Peptides for the Investigation of Conformational Changes Induced by Specific Phosphorylation Patterns
Gandhi, N. S., Kukić, P., Lippens, G. M., & Mancera, R. L. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-6598-4_3 · Cited by 9
pS396/pS404 (PHF1) tau vaccine outperforms pS199/pS202 (AT8) in rTg4510 tauopathy model
Hulse, J. P., Maphis, N. M., Peabody, J., Bondu, V., Chackerian, B., & Bhaskar, K. (2025) · npj Vaccines · doi:10.1038/s41541-025-01147-4 · Cited by 9
“Production of Q β -VLPs displaying phosphorylated S199/S202 (AT8) or phosphorylated S396/S404 (PHF1) tau peptides Q β VLPs were produced by purifying recombinantly expressed Q β protein produced in Escherichia coli as described previously 57,60,99 .”
Influential
Heterogeneous Dynamics of the Fuzzy Coat of Full-Length Phospho-Mimetic Tau Fibrils
Zhang, J. Y., Dregni, A. J., & Hong, M. (2026) · Journal of the American Chemical Society · doi:10.1021/jacs.5c18540 · Cited by 8
Effects of anti‐tau immunotherapy on reactive microgliosis, cerebral endotheliopathy, and cognitive function in an experimental model of cerebral malaria
Ndunge, O. B. A., Shikani, H. J., Dai, M., Freeman, B. D., & Desruisseaux, M. S. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15972 · Cited by 7
“Preventing tau pathology has been proposed as a potential therapeutic strategy for AD-like diseases (Boutajangout et al., 2011 ; Gu et al., 2013; Otvos Jr. et al., 1994).”
Background
Alteration of gene expression and protein solubility of the PI 5-phosphatase SHIP2 are correlated with Alzheimer’s disease pathology progression
Ando, K., Küçükali, F., Doeraene, E., Nagaraj, S., Antonelli, E. M., Htut, M. T., Yilmaz, Z., Kosa, A., Lopez‐Gutierrez, L., Quintanilla‐Sánchez, C., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02745-7 · Cited by 10
“Mouse monoclonal anti-pTau (Ser396 and Ser404) PHF1 antibody was provided by Dr. Peter Davies (Albert Einstein College of Medicine, NY) [68].”

Authors: Otvos, L., Feiner, L., Lang, E., Szendrei, G. I., Goedert, M., & Lee, V. M.
Affiliations: The Wistar Institute (US)
University of Pennsylvania (US)
MRC Laboratory of Molecular Biology (GB)
Corresponding author: Otvos, L.
ORCID: Otvos, L.
Goedert, M.
Venue: Journal of Neuroscience Research
Publisher: Wiley
Published: 1994-12-15
Volume: 39
Issue: 6
Pages: 669-673
ISSN: 0360-4012 (ISSN-L)
1097-4547
DOI: 10.1002/jnr.490390607
OpenAlex: W1984482388
Semantic Scholar: 4518f282e57a4d29fb281b9a658ed49720534f5d
Cited by: 488
References: 21
Citations by year: 2026: 14 · 2025: 27 · 2024: 14 · 2023: 11 · 2022: 13 · 2021: 11 · 2020: 13 · 2019: 13 · 2018: 6 · 2017: 13 · 2016: 16 · 2015: 12 · 2014: 7 · 2013: 24 · 2012: 23
FWCI: 7.47
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 3588 d)
Locations: Journal of Neuroscience Research (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01ag010670-02, 5p01ag009215-20)
National Institute on Aging (AG09215, AG 10670)
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 › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: tau protein, tau hyperphosphorylation, paired helical filaments, Alzheimer's disease, epitope mapping, CHO cells
MeSH terms: Alzheimer Disease, Amino Acid Sequence, Animals, Antibodies, Monoclonal, Epitopes, Enzyme-Linked Immunosorbent Assay, Cricetinae, Humans, Molecular Sequence Data, Peptides, Phosphorylation, Serine, Blotting, Western, CHO Cells, tau Proteins, DNA, Complementary

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Monoclonal antibody PHF‐1 recognizes tau protein phosphorylated at serine residues 396 and 404

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