F yn inhibition rescues established memory and synapse loss in A lzheimer mice

Kaufman, Adam C.; Salazar, Santiago V.; Haas, Laura T.; Yang, Jinhee; Kostylev, Mikhail A.; Jeng, Amanda T.; Robinson, Sophie A.; Gunther, Erik C.; van Dyck, Christopher H.; Nygaard, Haakon B.; Strittmatter, Stephen M.

doi:10.1002/ana.24394

Cited by 317Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

F yn inhibition rescues established memory and synapse loss in A lzheimer mice

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Kaufman, Adam C., Salazar, Santiago V., Haas, Laura T., Yang, Jinhee, Kostylev, Mikhail A., Jeng, Amanda T., Robinson, Sophie A., Gunther, Erik C. +3 more·2015·Annals of Neurology

DOI 10.1002/ana.24394PMC PMC4447598

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Abstract

Objective: Currently no effective disease‐modifying agents exist for the treatment of Alzheimer disease (AD). The Fyn tyrosine kinase is implicated in AD pathology triggered by amyloid‐ß oligomers (Aßo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncology compound, AZD0530, for AD. Methods: The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aßo signaling to Fyn, Pyk2, and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild‐type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, amyloid precursor protein (APP) metabolism, synaptic markers (SV2 and PSD‐95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting. Results: AZD0530 potently inhibits Fyn and prevents both Aßo‐induced Fyn signaling and downstream phosphorylation of the AD risk gene product Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Aß metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity. Interpretation: Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD. Ann Neurol 2015;77:953–971

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Aβ-induced Fyn signalling is associated with downstream Pyk2 phosphorylation.
“This reciprocal regulation is further supported by the observation that Aβ-induced Fyn signalling is associated with downstream Pyk2 phosphorylation [68].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [68]
The most common method to quantify synaptic density has been quantification of pre- and post-synaptic genes or proteins.
“the most common method to quantify synaptic density has been the quantification of pre-(e.g., synaptophysin [9], synapsin [8]) and post-synaptic (e.g., PSD-95 [10]) genes/proteins”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [10]
Work from the authors' group and others has shown that quantification of SV2A is similar to that of other markers of synaptic density in clinical samples and after drug challenge.
“work from our group and others has shown that quantification of SV2A is similar to that of other markers of synaptic density in clinical samples and after drug challenge”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [10]

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Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., & Ashe, K. H. (2006) · Nature · doi:10.1038/nature04533 · Cited by 2,769 · see citing works
Retracted
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Larson, M. E., Sherman, M. A., Amar, F., Nuvolone, M., Schneider, J. A., Bennett, D. A., Aguzzi, A., & Lesné, S. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1858-12.2012 · Cited by 274 · see citing works
Retracted
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864 · see citing works
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade
Jack, C. R., Knopman, D. S., Jagust, W. J., Shaw, L. M., Aisen, P. S., Weiner, M. W., Petersen, R. C., & Trojanowski, J. Q. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70299-6 · Cited by 4,806 · see citing works
Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336 · see citing works
Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo
Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J., & Selkoe, D. J. (2002) · Nature · doi:10.1038/416535a · Cited by 4,291 · see citing works
Triple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., & LaFerla, F. M. (2003) · Neuron · doi:10.1016/s0896-6273(03)00434-3 · Cited by 4,126 · see citing works
Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory
Shankar, G. M., Li, S., Mehta, T. H., Garcia-Munoz, A., Shepardson, N. E., Smith, I., Brett, F. M., Farrell, M. A., Rowan, M. J., Lemere, C. A., et al. (2008) · Nature Medicine · doi:10.1038/nm1782 · Cited by 3,685 · see citing works
Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6448 · Cited by 3,506 · see citing works
TREM2 Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020 · see citing works
Variant of TREM2 Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558 · see citing works
Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects
Shaw, L. M., Vanderstichele, H., Knapik‐Czajka, M., Clark, C. M., Aisen, P. S., Petersen, R. C., Blennow, K., Soares, H., Simon, A., Lewczuk, P., et al. (2009) · Annals of Neurology · doi:10.1002/ana.21610 · Cited by 2,065 · see citing works
Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective
Tanzi, R. E., & Bertram, L. (2005) · Cell · doi:10.1016/j.cell.2005.02.008 · Cited by 1,849 · see citing works
Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models
Ittner, L. M., Ke, Y. D., Delerue, F., Bi, M., Gladbach, A., van Eersel, J., Wölfing, H., Chieng, B. C., Christie, M. J., Napier, I. A., et al. (2010) · Cell · doi:10.1016/j.cell.2010.06.036 · Cited by 1,821 · see citing works
A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline
Jonsson, T., Atwal, J. K., Steinberg, S., Snaedal, J., Jonsson, P. V., Bjornsson, S., Stefansson, H., Sulem, P., Gudbjartsson, D., Maloney, J., et al. (2012) · Nature · doi:10.1038/nature11283 · Cited by 1,738 · see citing works
Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP
Lewis, J., Dickson, D. W., Lin, W.-L., Chisholm, L., Corral, A., Jones, G., Yen, S.-H., Sahara, N., Skipper, L., Yager, D., et al. (2001) · Science · doi:10.1126/science.1058189 · Cited by 1,611 · see citing works
Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase
Jankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh019 · Cited by 1,575 · see citing works
Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers
Laurén, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W., & Strittmatter, S. M. (2009) · Nature · doi:10.1038/nature07761 · Cited by 1,560 · see citing works
Self-citation
Alzheimer’s Disease: The Challenge of the Second Century
Holtzman, D. M., Morris, J. C., & Goate, A. M. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002369 · Cited by 1,424 · see citing works
Impaired Long-Term Potentiation, Spatial Learning, and Hippocampal Development in fyn Mutant Mice
Grant, S. G. N., O’Dell, T. J., Karl, K. A., Stein, P. L., Soriano, P. M., & Kandel, E. R. (1992) · Science · doi:10.1126/science.1361685 · Cited by 1,154 · see citing works
Transient and persistent dendritic spines in the neocortex in vivo
Holtmaat, A. J. G. D., Trachtenberg, J. T., Wilbrecht, L., Shepherd, G. M., Zhang, X., Knott, G. W., & Svoboda, K. (2005) · Neuron · doi:10.1016/j.neuron.2005.01.003 · Cited by 1,131 · see citing works
2012 Alzheimer's disease facts and figures Alzheimer's Association ∗
Thies, W. H., & Bleiler, L. (2012) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2012.02.001 · Cited by 984 · see citing works
Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons
Um, J. W., Nygaard, H. B., Heiss, J. K., Kostylev, M. A., Stagi, M., Vortmeyer, A. O., Wısnıewskı, T., Gunther, E. C., & Strittmatter, S. M. (2012) · Nature Neuroscience · doi:10.1038/nn.3178 · Cited by 654 · see citing works
Self-citation
Amyloid-β/Fyn–Induced Synaptic, Network, and Cognitive Impairments Depend on Tau Levels in Multiple Mouse Models of Alzheimer's Disease
Roberson, E. D., Halabisky, B., Yoo, J. W., Yao, J., Chin, J., Yan, F., Wu, T., Hamto, P., Devidze, N., Yu, G.-Q., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4152-10.2011 · Cited by 654 · see citing works
Mice Lacking Metabotropic Glutamate Receptor 5 Show Impaired Learning and Reduced CA1 Long-Term Potentiation (LTP) But Normal CA3 LTP
Lu, Y.-M., Jia, Z., Janus, C., Henderson, J. T., Gerlai, R., Wojtowicz, J. M., & Roder, J. C. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-13-05196.1997 · Cited by 634 · see citing works
Metabotropic Glutamate Receptor 5 Is a Coreceptor for Alzheimer Aβ Oligomer Bound to Cellular Prion Protein
Um, J. W., Kaufman, A. C., Kostylev, M., Heiss, J. K., Stagi, M., Takahashi, H., Kerrisk, M. E., Vortmeyer, A., Wisniewski, T., Koleske, A. J., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.036 · Cited by 572 · see citing works
Self-citation
Tau interacts with src-family non-receptor tyrosine kinases
Lee, G. S., Newman, S. T., Gard, D. L., Band, H., & Panchamoorthy, G. (1998) · Journal of Cell Science · doi:10.1242/jcs.111.21.3167 · Cited by 445 · see citing works
Memory Impairment in Transgenic Alzheimer Mice Requires Cellular Prion Protein
Gimbel, D. A., Nygaard, H. B., Coffey, E. E., Gunther, E. C., Laurén, J., Gimbel, Z. A., & Strittmatter, S. M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.0395-10.2010 · Cited by 418 · see citing works
Self-citation
Phosphorylation of Tau by Fyn: Implications for Alzheimer's Disease
Lee, G. S., Thangavel, R., Sharma, V. M., Litersky, J. M., Bhaskar, K., Fang, S. M., Lana, H., Andreadis, A., Hoesen, G. W. V., & Ksiȩżak-Reding, H. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4162-03.2004 · Cited by 414 · see citing works
N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a Novel, Highly Selective, Orally Available, Dual-Specific c-Src/Abl Kinase Inhibitor
Hennequin, L. F., Allen, J. M., Breed, J., Curwen, J., Fennell, M., Green, T. P., der Brempt, C. L., Morgentin, R., Norman, R. A., Olivier, A., et al. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm060434q · Cited by 365 · see citing works
A CD36-initiated Signaling Cascade Mediates Inflammatory Effects of β-Amyloid
Moore, K. J., El Khoury, J., Medeiros, L. A., Terada, K., Geula, C., Luster, A. D., & Freeman, M. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208788200 · Cited by 327 · see citing works
Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer’s disease
Chin, J., Palop, J. J., Puoliväli, J., Massaro, C., Bien-Ly, N., Gerstein, H., Scearce-Levie, K., Masliah, E., & Mucke, L. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.2980-05.2005 · Cited by 312 · see citing works
Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration
Okigaki, M., Davis, C., Falasca, M., Harroch, S., Felsenfeld, D. P., Sheetz, M. P., & Schlessinger, J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834348100 · Cited by 299 · see citing works
P1‐071: Intensity of dementia through latent variable modelling (I‐DeLV) in the AIBL cohort
Burnham, S. C., Graham, P. L., Wilson, B., Ames, D. J., Macaulay, L. S., Martins, R. N., Masters, C. L., Maruff, P. T., Rowe, C. C., Szoeke, C. E. I., et al. (2012) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2012.05.347 · Cited by 292 · see citing works
Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites
Freir, D. B., Nicoll, A. J., Klyubin, I. V., Panico, S., Donald, J. M. M., Risse, E., Asante, E. A., Farrow, M. A., Sessions, R. B., Saibil, H. R., et al. (2011) · Nature Communications · doi:10.1038/ncomms1341 · Cited by 290 · see citing works
CAKβ/Pyk2 Kinase Is a Signaling Link for Induction of Long-Term Potentiation in CA1 Hippocampus
Huang, Y.-Q., Lu, W.-Y., Ali, D. W., Pelkey, K. A., Pitcher, G. M., Lu, Y. M., Aoto, H., Roder, J. C., Sasaki, T., Salter, M. W., et al. (2001) · Neuron · doi:10.1016/s0896-6273(01)00220-3 · Cited by 274 · see citing works
A Technique for Serial Collection of Cerebrospinal Fluid from the Cisterna Magna in Mouse
Liu, L., & Duff, K. (2008) · Journal of Visualized Experiments · doi:10.3791/960 · Cited by 268 · see citing works
Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530
Green, T. P., Fennell, M., Whittaker, R., Curwen, J., Jacobs, V., Allen, J., Logie, A., Hargreaves, J., Hickinson, D. M., Wilkinson, R. W., et al. (2009) · Molecular Oncology · doi:10.1016/j.molonc.2009.01.002 · Cited by 238 · see citing works
Alzheimer's Disease Brain-Derived Amyloid-β-Mediated Inhibition of LTPIn VivoIs Prevented by Immunotargeting Cellular Prion Protein
Barry, A. E., Klyubin, I., Mc Donald, J. M., Mably, A. J., Farrell, M. A., Scott, M., Walsh, D. M., & Rowan, M. J. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6500-10.2011 · Cited by 237 · see citing works
Disease-related Modifications in Tau Affect the Interaction between Fyn and Tau
Bhaskar, K., Yen, S.-H. C., & Lee, G. S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505895200 · Cited by 223 · see citing works
Metabotropic Glutamate Receptor 1-Induced Upregulation of NMDA Receptor Current: Mediation through the Pyk2/Src-Family Kinase Pathway in Cortical Neurons
Heidinger, V., Manzerra, P., Wang, X. Q., Strasser, U., Yu, S. P., Choi, D. W., & Behrens, M. M. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-13-05452.2002 · Cited by 221 · see citing works
Altered synaptic dynamics during normal brain aging.
Mostany, R., Anstey, J. E., Crump, K. L., Maco, B., Knott, G., & Portera-Cailliau, C. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.4825-12.2013 · Cited by 179 · see citing works
Expression of a novel form of the fyn proto-oncogene in hematopoietic cells.
Mp, C., & Perlmutter, R. (1989) · PubMed · Cited by 178 · see citing works
Fyn Kinase Modulates Synaptotoxicity, But Not Aberrant Sprouting, in Human Amyloid Precursor Protein Transgenic Mice
Chin, J., Palop, J. J., Yu, G.-Q., Kojima, N., Masliah, E., & Mucke, L. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.0277-04.2004 · Cited by 161 · see citing works
Phase II Trial of Saracatinib (AZD0530), an Oral SRC-inhibitor for the Treatment of Patients with Hormone Receptor-negative Metastatic Breast Cancer
Gucalp, A., Sparano, J. A., Caravelli, J. F., Santamauro, J. T., Patil, S. N., Abbruzzi, A., Pellegrino, C. M., Bromberg, J., Dang, C. T., Theodoulou, M., et al. (2011) · Clinical Breast Cancer · doi:10.1016/j.clbc.2011.03.021 · Cited by 159 · see citing works
RAFTK/Pyk2 Activation Is Mediated by Trans-acting Autophosphorylation in a Src-independent Manner
Park, S., Avraham, H. K., & Avraham, S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313527200 · Cited by 147 · see citing works
CD36 Signals to the Actin Cytoskeleton and Regulates Microglial Migration via a p130Cas Complex
Stuart, L. M., Bell, S. A., Stewart, C. R., Silver, J. M., Richard, J., Goss, J. L., Tseng, A. A., Zhang, A., Khoury, J. B. E., & Moore, K. J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702887200 · Cited by 115 · see citing works
Anatomical Plasticity of Adult Brain Is Titrated by Nogo Receptor 1
Akbik, F. V., Bhagat, S. M., Patel, P. R., Cafferty, W. B. J., & Strittmatter, S. M. (2013) · Neuron · doi:10.1016/j.neuron.2012.12.027 · Cited by 113 · see citing works
Self-citation
Phase I Safety, Pharmacokinetics, and Inhibition of Src Activity Study of Saracatinib in Patients with Solid Tumors
Baselga, J. M., Cervantes, A. M. R., Martinelli, E., Chirivella, I., Hoekman, K., Hurwitz, H. I., Jodrell, D. I., Hamberg, P., Casado, E., Elvin, P., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-0748 · Cited by 109 · see citing works
Therapeutic Molecules and Endogenous Ligands Regulate the Interaction between Brain Cellular Prion Protein (PrPC) and Metabotropic Glutamate Receptor 5 (mGluR5)
Haas, L. T., Kostylev, M. A., & Strittmatter, S. M. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.584342 · Cited by 87 · see citing works
Self-citation
Postsynaptic Clustering and Activation of Pyk2 by PSD-95
Bartos, J. A., Ulrich, J. D., Li, H., Beazely, M. A., Chen, Y., MacDonald, J. F., & Hell, J. W. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.4992-08.2010 · Cited by 86 · see citing works
Interaction of the Tyrosine Kinase Pyk2 with the N-Methyl-d-aspartate Receptor Complex via the Src Homology 3 Domains of PSD-95 and SAP102
Seabold, G. K., Burette, A., Lim, I. A., Weinberg, R. J., & Hell, J. W. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212825200 · Cited by 83 · see citing works
Amyloid-β42 Interacts Mainly with Insoluble Prion Protein in the Alzheimer Brain
Zou, W., Xiao, X., Yuan, J., Puoti, G., Fujioka, H., Wang, X., Richardson, S. L., Zhou, X., Zou, R. S., Li, S., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.199356 · Cited by 80 · see citing works
Phase II study of saracatinib (AZD0530) for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).
Fury, M. G., Baxi, S. S., Shen, R., Kelly, K. W., Lipson, B. L., Carlson, D. L., Stambuk, H. E., Haque, S. S., & Pfister, D. G. (2011) · PubMed · Cited by 75 · see citing works
Tyrosine phosphorylation of tau accompanies disease progression in transgenic mouse models of tauopathy
Bhaskar, K., Hobbs, G. A., Yen, S.-H., & Lee, G. S. (2010) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2010.01103.x · Cited by 74 · see citing works
Phase II study of the Src kinase inhibitor saracatinib (AZD0530) in metastatic melanoma
Gangadhar, T. C., Clark, J. I., Karrison, T. G., & Gajewski, T. F. (2012) · Investigational New Drugs · doi:10.1007/s10637-012-9897-4 · Cited by 57 · see citing works
A phase II trial of the Src kinase inhibitor saracatinib (AZD0530) in patients with metastatic or locally advanced gastric or gastro esophageal junction (GEJ) adenocarcinoma: a trial of the PMH phase II consortium
MacKay, H. J., Au, H., McWhirter, E., Alcindor, T., Jarvi, A., MacAlpine, K., Wang, L. E., Wright, J. J., & Oza, A. M. (2011) · Investigational New Drugs · doi:10.1007/s10637-011-9650-4 · Cited by 53 · see citing works
A phase I/II study of the Src inhibitor saracatinib (AZD0530) in combination with gemcitabine in advanced pancreatic cancer
Renouf, D. J., Moore, M. J., Hedley, D. W., Gill, S., Jonker, D. J., Chen, E. X., Walde, D., Goel, R., Southwood, B., Gauthier, I. C., et al. (2010) · Investigational New Drugs · doi:10.1007/s10637-010-9611-3 · Cited by 53 · see citing works
A Technique for Serial Collection of Cerebrospinal Fluid from the Cisterna Magna in Mouse
Liu, L., & Duff, K. (2008) · Journal of Visualized Experiments · doi:10.3791/960-v · Cited by 48 · see citing works
The T cell receptor-mediated phosphorylation of Pyk2 tyrosines 402 and 580 occurs via a distinct mechanism than other receptor systems
Collins, M., Tremblay, M. M., Chapman, N. M., Curtiss, M. L., Rothman, P. B., & Houtman, J. C. D. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.0409227 · Cited by 32 · see citing works
T cell receptor activation leads to two distinct phases of Pyk2 activation and actin cytoskeletal rearrangement in human T cells
Collins, M., Bartelt, R. R., & Houtman, J. C. D. (2010) · Molecular Immunology · doi:10.1016/j.molimm.2010.03.009 · Cited by 27 · see citing works

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Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988 · see citing works
“Accordingly, inhibition of Fyn improved the cognitive deficits in transgenic mice with Aβ and tau depositions.(144,145) PET and CSF tests also indicate the synergy between Aβ and tau, which leads to brain dysfunction and cognitive impairment.”
Background
The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade
Cline, E. N., Bicca, M. A., Viola, K. L., & Klein, W. L. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179941 · Cited by 870 · see citing works
Interaction between Aβ and Tau in the Pathogenesis of Alzheimer’s Disease
Zhang, H., Wei, W., Zhao, M., Ma, L., Jiang, X., Pei, H., Cao, Y., & Li, H. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.57078 · Cited by 689 · see citing works
Epileptic activity in Alzheimer’s disease: Causes and clinical relevance
Vossel, K. A., Tartaglia, M. C., Nygaard, H. B., Zeman, A. Z., & Miller, B. L. (2017) · The Lancet Neurology · doi:10.1016/s1474-4422(17)30044-3 · Cited by 590 · see citing works
Self-citation
Imaging synaptic density in the living human brain
Finnema, S. J., Nabulsi, N. B., Eid, T., Detyniecki, K., Lin, S.-F., Chen, M.-K., Dhaher, R., Matuskey, D., Baum, E., Holden, D., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf6667 · Cited by 575 · see citing works
Synaptic degeneration in Alzheimer disease
Tzioras, M., McGeachan, R. I., Durrant, C. S., & Spires-Jones, T. L. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-022-00749-z · Cited by 504 · see citing works
Drug combination therapy increases successful drug repositioning
Sun, W., Sanderson, P. E. J., & Zheng, W. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2016.05.015 · Cited by 438 · see citing works
Synaptic Impairment in Alzheimer’s Disease: A Dysregulated Symphony
Forner, S., Baglietto-Vargas, D., Martini, A. C., Trujillo-Estrada, L., & LaFerla, F. M. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.04.002 · Cited by 430 · see citing works
Soluble amyloid-Î² oligomers as synaptotoxins leading to cognitive impairment in Alzheimerâ€™s disease
Ferreira, S. T., Lourenco, M. V., Oliveira, M. M., & De Felice, F. G. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00191 · Cited by 373 · see citing works
Genes associated with Alzheimer&#39;s disease: an overview and current status
Giri, M., Lü, Y., & Zhang, M. (2016) · Clinical Interventions in Aging · doi:10.2147/cia.s105769 · Cited by 311 · see citing works
BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease
Moussa‐Pacha, N. M., Abdin, S. M., Omar, H. A., Alniss, H. Y., & Al‐Tel, T. H. (2019) · Medicinal Research Reviews · doi:10.1002/med.21622 · Cited by 308 · see citing works
Synthesis and Preclinical Evaluation of 11 C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain
Nabulsi, N. B., Mercier, J., Holden, D., Carré, S., Najafzadeh, S., Vandergeten, M.-C., Lin, S.-F., Deo, A., Price, N., Wood, M., et al. (2016) · Journal of Nuclear Medicine · doi:10.2967/jnumed.115.168179 · Cited by 296 · see citing works
Advances in developing novel therapeutic strategies for Alzheimer’s disease
Cao, J., Hou, J., Ping, J., & Cai, D. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0299-8 · Cited by 283 · see citing works
Molecular Pathogenesis of the Tauopathies
Götz, J., Halliday, G., & Nisbet, R. M. (2019) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-012418-012936 · Cited by 276 · see citing works
Tau-based therapies in neurodegeneration: opportunities and challenges
Li, C., & Götz, J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.155 · Cited by 272 · see citing works
Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia
Panicker, N., Sarkar, S., Harischandra, D. S., Neal, M. P., Kam, T., Jin, H., Saminathan, H., Langley, M. R., Charli, A., Samidurai, M., et al. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20182191 · Cited by 255 · see citing works
Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase
Xiao, L., Salem, J., Clauß, S., Hanley, A., Bapat, A. C., Hulsmans, M., Iwamoto, Y., Wojtkiewicz, G. R., Çetinbaş, M., Schloss, M. J., et al. (2020) · Circulation · doi:10.1161/circulationaha.120.049210 · Cited by 251 · see citing works
The role of pathological tau in synaptic dysfunction in Alzheimer’s diseases
Wu, M., Zhang, M., Yin, X., Chen, K., Hu, Z., Zhou, Q., Cao, X., Chen, Z., & Liu, D. (2021) · Translational Neurodegeneration · doi:10.1186/s40035-021-00270-1 · Cited by 241 · see citing works
Kinetic evaluation and test–retest reproducibility of [ 11 C]UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans
Finnema, S. J., Nabulsi, N. B., Mercier, J., Lin, S.-F., Chen, M.-K., Matuskey, D., Gallezot, J.-D., Henry, S., Hannestad, J., Huang, Y., et al. (2018) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x17724947 · Cited by 218 · see citing works
Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration
Daher, J. P. L., Abdelmotilib, H., Hu, X., Volpicelli‐Daley, L. A., Moehle, M. S., Fraser, K. B., Needle, E., Chen, Y., Steyn, S. J., Galatsis, P., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.660001 · Cited by 212 · see citing works
Melatonin regulates Aβ production/clearance balance and Aβ neurotoxicity: A potential therapeutic molecule for Alzheimer’s disease
Li, Y., Zhang, J., Wan, J., Liu, A., & Sun, J. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110887 · Cited by 212 · see citing works
New Approaches for the Treatment of Alzheimer’s Disease
Fish, P. V., Steadman, D., Bayle, E. D., & Whiting, P. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2018.11.034 · Cited by 189 · see citing works
Actin dynamics and cofilin‐actin rods in alzheimer disease
Bamburg, J. R., & Bernstein, B. W. (2016) · Cytoskeleton · doi:10.1002/cm.21282 · Cited by 181 · see citing works
Somatodendritic accumulation of Tau in Alzheimer's disease is promoted by Fyn‐mediated local protein translation
Li, C., & Götz, J. (2017) · The EMBO Journal · doi:10.15252/embj.201797724 · Cited by 178 · see citing works
The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis?
Dourlen, P., Kilinc, D., Malmanche, N., Chapuis, J., & Lambert, J.-C. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02004-0 · Cited by 168 · see citing works
Tau Oligomers: The Toxic Player at Synapses in Alzheimer’s Disease
Guerrero-Muñoz, M. J., Gerson, J., & Castillo-Carranza, D. L. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00464 · Cited by 168 · see citing works
A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer’s disease
Nygaard, H. B., Wagner, A. F., Bowen, G. S., Good, S. P., MacAvoy, M. G., Strittmatter, K. A., Kaufman, A. C., Rosenberg, B. J., Sekine-Konno, T., Varma, P., et al. (2015) · Alzheimer s Research & Therapy · doi:10.1186/s13195-015-0119-0 · Cited by 164 · see citing works
Self-citation
Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies
Limorenko, G., & Lashuel, H. A. (2021) · Chemical Society Reviews · doi:10.1039/d1cs00127b · Cited by 162 · see citing works
Targeting Fyn Kinase in Alzheimer’s Disease
Nygaard, H. B. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.06.004 · Cited by 162 · see citing works
Self-citation
The synapse as a treatment avenue for Alzheimer’s Disease
Peng, L., Bestard‐Lorigados, I., & Song, W. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01565-z · Cited by 158 · see citing works
Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer’s disease? From preclinical studies to the clinical trials
Basheer, N., Smolek, T., Hassan, I., Liu, F., Iqbal, K., Zilka, N., & Novak, P. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02113-z · Cited by 159 · see citing works
Polysaccharides from Ganoderma lucidum Promote Cognitive Function and Neural Progenitor Proliferation in Mouse Model of Alzheimer's Disease
Huang, S., Mao, J., Ding, K., Zhou, Y., Zeng, X., Yang, W., Wang, P., Zhao, C., Yao, J., Xia, P., et al. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2016.12.007 · Cited by 154 · see citing works
Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer’s disease
Haas, L. T., Salazar, S. V., Kostylev, M. A., Um, J. W., Kaufman, A. C., & Strittmatter, S. M. (2015) · Brain · doi:10.1093/brain/awv356 · Cited by 140 · see citing works
Self-citation
Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease
van Dyck, C. H., Nygaard, H. B., Chen, K., Donohue, M., Raman, R., Rissman, R. A., Brewer, J. B., Koeppe, R. A., Chow, T. W., Rafii, M. S., et al. (2019) · JAMA Neurology · doi:10.1001/jamaneurol.2019.2050 · Cited by 144 · see citing works
Self-citation
Small Molecule Kinase Inhibitors for the Treatment of Brain Cancer
Heffron, T. P. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00618 · Cited by 141 · see citing works
Exploration of databases and methods supporting drug repurposing: a comprehensive survey
Tanoli, Z., Seemab, U., Scherer, A., Wennerberg, K., Tang, J., & Vähä-Koskela, M. (2021) · Briefings in Bioinformatics · doi:10.1093/bib/bbaa003 · Cited by 131 · see citing works
New Insights Into Drug Discovery Targeting Tau Protein
Soeda, Y., & Takashima, A. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.590896 · Cited by 133 · see citing works
Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes
Haas, L. T., Salazar, S. V., Smith, L. M., Zhao, H. R., Cox, T. O., Herber, C. S., Degnan, A. P., Balakrishnan, A., Macor, J. E., Albright, C. F., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.06.023 · Cited by 117 · see citing works
Self-citation
Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain
He, X., Li, L., Xian, W., Li, M., Zhang, L., Xu, J., Pei, Z., Zheng, H., & Hu, X. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02199-8 · Cited by 116 · see citing works
Association of cancer and Alzheimer's disease risk in a national cohort of veterans
Frain, L., Swanson, D., Cho, K., Gagnon, D., Lu, K. P., Betensky, R. A., & Driver, J. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2017.04.012 · Cited by 115 · see citing works
Precision pharmacology for Alzheimer’s disease
Hampel, H. J., Vergallo, A., Aguilar, L. F., Benda, N., Broich, K., Cuello, A. C., Cummings, J. L., Dubois, B., Federoff, H. J., Fiandaca, M. S., et al. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.02.014 · Cited by 112 · see citing works
Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q
Spurrier, J. M., Nicholson, L., Fang, X. T., Stoner, A. J., Toyonaga, T., Holden, D., Siegert, T. R., Laird, W., Allnutt, M. A., Chiasseu, M., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abi8593 · Cited by 102 · see citing works
Self-citation
Improved modeling of human AD with an automated culturing platform for iPSC neurons, astrocytes and microglia
Bassil, R., Shields, K., Granger, K., Zein, I., Ng, S., & Chih, B. (2021) · Nature Communications · doi:10.1038/s41467-021-25344-6 · Cited by 106 · see citing works
In vivo evidence of lower synaptic vesicle density in schizophrenia
Radhakrishnan, R., Skosnik, P. D., Ranganathan, M., Naganawa, M., Toyonaga, T., Finnema, S., Hillmer, A. T., Esterlis, I., Huang, Y., Nabulsi, N., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01184-0 · Cited by 100 · see citing works
Phosphorylation of tau at Y18, but not tau-fyn binding, is required for tau to modulate NMDA receptor-dependent excitotoxicity in primary neuronal culture
Miyamoto, T., Stein, L. R., Thomas, R., Djukic, B., Taneja, P., Knox, J. A., Vossel, K. A., & Mucke, L. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0176-x · Cited by 100 · see citing works
Targeting tau: clinical trials and novel therapeutic approaches
VandeVrede, L., Boxer, A. L., & Polydoro, M. (2020) · Neuroscience Letters · doi:10.1016/j.neulet.2020.134919 · Cited by 90 · see citing works
Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer’s Disease
Toniolo, S., Sen, A., & Husain, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239318 · Cited by 94 · see citing works
Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegeneration
Socodato, R., Portugal, C. C., Canedo, T., Rodrigues, A., Almeida, T. O., Henriques, J. F., Vaz, S. H., Magalhães, J., Silva, C. M., Baptista, F. I., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107796 · Cited by 94 · see citing works
The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology
Tseng, J.-H., Xie, L., Song, S., Xie, Y., Allen, L., Ajit, D., Hong, J.-S., Chen, X., Meeker, R. B., & Cohen, T. J. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.07.082 · Cited by 93 · see citing works
The Role of MAPT in Neurodegenerative Diseases: Genetics, Mechanisms and Therapy
Zhang, C., Xing, A., Tan, M., Tan, L., & Yu, J. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9415-8 · Cited by 91 · see citing works
Critical residues involved in tau binding to fyn: implications for tau phosphorylation in Alzheimer’s disease
Lau, D. H. W., Hogseth, M., Phillips, E. C., O’Neill, M. J., Pooler, A. M., Noble, W. J., & Hanger, D. P. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0317-4 · Cited by 91 · see citing works
Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease
Salazar, S. V., & Strittmatter, S. M. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.09.062 · Cited by 90 · see citing works
Self-citation
Fyn Tyrosine Kinase as Harmonizing Factor in Neuronal Functions and Dysfunctions
Matrone, C., Petrillo, F., Nasso, R., & Ferretti, G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124444 · Cited by 86 · see citing works
AP39, a Mitochondria‐Targeted Hydrogen Sulfide Donor, Supports Cellular Bioenergetics and Protects against Alzheimer’s Disease by Preserving Mitochondrial Function in APP/PS1 Mice and Neurons
Zhao, F., Fang, F., Qiao, P., Yan, N., Gao, D., & Yan, Y. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/8360738 · Cited by 88 · see citing works
GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways
Demuro, S., Martino, R. M. C. D., Ortega, J. A., & Cavalli, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22169098 · Cited by 85 · see citing works
Synaptotoxic Signaling by Amyloid Beta Oligomers in Alzheimer's Disease Through Prion Protein and mGluR5
Brody, A. H., & Strittmatter, S. M. (2017) · Advances in pharmacology · doi:10.1016/bs.apha.2017.09.007 · Cited by 83 · see citing works
Self-citation
Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies
Silva, M. C., & Haggarty, S. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238948 · Cited by 87 · see citing works
Prion Protein as a Toxic Acceptor of Amyloid-β Oligomers
Purro, S. A., Nicoll, A. J., & Collinge, J. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.11.020 · Cited by 80 · see citing works
Fyn Kinase Controls Tau Aggregation In Vivo
Briner, A., Götz, J., & Polanco, J. C. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108045 · Cited by 80 · see citing works
Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery
Wu, X., Yang, Z., Zou, J., Gao, H., Shao, Z., Li, C., & Lei, P. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02179-x · Cited by 88 · see citing works
Aβ oligomers promote oligodendrocyte differentiation and maturation via integrin β1 and Fyn kinase signaling
Quintela-López, T., Ortiz-Sanz, C., Serrano-Regal, M. P., Gaminde-Blasco, A., Valero, J., Baleriola, J., Sánchez-Gómez, M. V., Matute, C., & Alberdi, E. (2019) · Cell Death & Disease · doi:10.1038/s41419-019-1636-8 · Cited by 80 · see citing works
In Vivo Synaptic Density Imaging with 11 C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease
Toyonaga, T., Smith, L. M., Finnema, S. J., Gallezot, J.-D., Naganawa, M., Bini, J., Mulnix, T., Cai, Z., Ropchan, J., Huang, Y., et al. (2019) · Journal of Nuclear Medicine · doi:10.2967/jnumed.118.223867 · Cited by 79 · see citing works
Self-citation
Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr 682 -phosphorylated APP βCTF
Im, E., Jiang, Y., Stavrides, P. H., Darji, S., Erdjument-Bromage, H., Neubert, T. A., Choi, J. Y., Wegiel, J., Lee, J.-H., & Nixon, R. A. (2023) · Science Advances · doi:10.1126/sciadv.adg1925 · Cited by 80 · see citing works
Alzheimer's Disease Risk Factor Pyk2 Mediates Amyloid-β-Induced Synaptic Dysfunction and Loss
Salazar, S. V., Cox, T. O., Lee, S., Brody, A. H., Chyung, A. S., Haas, L. T., & Strittmatter, S. M. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.1873-18.2018 · Cited by 77 · see citing works
Self-citation
Oligomers of Amyloid β Prevent Physiological Activation of the Cellular Prion Protein-Metabotropic Glutamate Receptor 5 Complex by Glutamate in Alzheimer Disease
Haas, L. T., & Strittmatter, S. M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.720664 · Cited by 75 · see citing works
Self-citation
Daily alcohol intake triggers aberrant synaptic pruning leading to synapse loss and anxiety-like behavior
Socodato, R., Henriques, J. F., Portugal, C. C., Almeida, T. O., Tedim-Moreira, J., Alves, R. L., Canedo, T., Silva, C., Magalhães, A., Summavielle, T., et al. (2020) · Science Signaling · doi:10.1126/scisignal.aba5754 · Cited by 76 · see citing works
Integrative Analysis of Hippocampus Gene Expression Profiles Identifies Network Alterations in Aging and Alzheimer’s Disease
Lanke, V., Moolamalla, S. T. R., Roy, D., & Vinod, P. K. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00153 · Cited by 76 · see citing works
Targeting NLRP3 inflammasome for neurodegenerative disorders
Yao, J., Wang, Z., Song, W., & Zhang, Y. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02239-0 · Cited by 75 · see citing works
Prions activate a p38 MAPK synaptotoxic signaling pathway
Fang, C., Wu, B., Le, N. T. T., Imberdis, T., Mercer, R. C. C., & Harris, D. A. (2018) · PLoS Pathogens · doi:10.1371/journal.ppat.1007283 · Cited by 72 · see citing works
Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva
Williams, E., Bagarova, J., Kerr, G., Xia, D.-D., Place, E., Dey, D., Shen, Y., Bocobo, G. A., Mohedas, A. H., Huang, X., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.95042 · Cited by 71 · see citing works
Noncanonical Metabotropic Glutamate Receptor 5 Signaling in Alzheimer's Disease
Abd‐Elrahman, K. S., & Ferguson, S. S. G. (2021) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-021821-091747 · Cited by 71 · see citing works
Tyrosine kinase Fyn promotes osteoarthritis by activating the β-catenin pathway
Li, K., Zhang, Y., Zhang, Y., Jiang, W., Shen, J., Xu, S., Cai, D., Shen, J., Huang, B., Li, M., et al. (2018) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2017-212658 · Cited by 72 · see citing works
Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic Tauopathy
Tang, S. J., Fesharaki‐Zadeh, A., Takahashi, H., Nies, S. H., Smith, L. M., Luo, A., Chyung, A. S., Chiasseu, M., & Strittmatter, S. M. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-00976-9 · Cited by 72 · see citing works
Self-citation
Role of the Fyn-PKCδ signaling in SE-induced neuroinflammation and epileptogenesis in experimental models of temporal lobe epilepsy
Sharma, S., Carlson, S., Puttachary, S., Sarkar, S., Showman, L. J., Putra, M. R. E., Kanthasamy, A. G., & Thippeswamy, T. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.11.008 · Cited by 70 · see citing works
Tyrosine phosphorylation regulates hnRNPA2 granule protein partitioning and reduces neurodegeneration
Ryan, V. H., Perdikari, T. M., Naik, M. T., Saueressig, C. F., Lins, J., Dignon, G. L., Mittal, J., Hart, A. C., & Fawzi, N. L. (2020) · The EMBO Journal · doi:10.15252/embj.2020105001 · Cited by 69 · see citing works
PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer's disease
Giralt, A., de Pins, B., Cifuentes-Díaz, C., López-Molina, L., Farah, A. T., Tible, M., Deramecourt, V., Arold, S. T., Ginés, S., Hugon, J., et al. (2018) · Experimental Neurology · doi:10.1016/j.expneurol.2018.05.020 · Cited by 64 · see citing works
Src family kinases (SFKs): critical regulators of microglial homeostatic functions and neurodegeneration in Parkinson's and Alzheimer's diseases
Portugal, C. C., Almeida, T. O., Socodato, R., & Relvas, J. B. (2021) · FEBS Journal · doi:10.1111/febs.16197 · Cited by 61 · see citing works
The Non-receptor Tyrosine Kinase Pyk2 in Brain Function and Neurological and Psychiatric Diseases
de Pins, B., Mendes, T., Giralt, A., & Girault, J. (2021) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2021.749001 · Cited by 59 · see citing works
Frontotemporal dementia mutant Tau promotes aberrant Fyn nanoclustering in hippocampal dendritic spines
Padmanabhan, P., Martínez‐Mármol, R., Xia, D., Götz, J., & Meunier, F. A. (2019) · eLife · doi:10.7554/elife.45040 · Cited by 61 · see citing works
Alzheimer’s Disease – The Past, the Present and the Future
Botchway, B. O. A. (2017) · Science Journal of Clinical Medicine · doi:10.11648/j.sjcm.20170601.11 · Cited by 60 · see citing works
Synthesis and in vivo evaluation of [18F]UCB-J for PET imaging of synaptic vesicle glycoprotein 2A (SV2A)
Li, S., Cai, Z., Zhang, W., Holden, D., Lin, S.-F., Finnema, S. J., Shirali, A., Ropchan, J., Carre, S., Mercier, J., et al. (2019) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-019-04357-w · Cited by 59 · see citing works
Pyk2 Signaling through Graf1 and RhoA GTPase Is Required for Amyloid-β Oligomer-Triggered Synapse Loss
Lee, S., Salazar, S. V., Cox, T. O., & Strittmatter, S. M. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.2983-18.2018 · Cited by 55 · see citing works
Self-citation
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Authors: Kaufman, A. C., Salazar, S. V., Haas, L. T., Yang, J., Kostylev, M. A., Jeng, A. T., Robinson, S. A., Gunther, E. C., van Dyck, C. H., Nygaard, H. B., & Strittmatter, S. M.
Affiliations: Yale University (US)
Department of Psychiatry Yale University School of Medicine New Haven CT
Corresponding author: Strittmatter, Stephen M.
ORCID: Kaufman, Adam C.
Salazar, Santiago V.
Yang, Jinhee
Kostylev, Mikhail A.
Robinson, Sophie A.
Nygaard, Haakon B.
Strittmatter, Stephen M.
Venue: Annals of Neurology
Publisher: Wiley
Published: 2015-03-21
Volume: 77
Issue: 6
Pages: 953-971
ISSN: 0364-5134 (ISSN-L)
1531-8249
DOI: 10.1002/ana.24394
PMC: PMC4447598
OpenAlex: W1725757145
Cited by: 314
References: 62
Citations by year: 2026: 16 · 2025: 13 · 2024: 19 · 2023: 25 · 2022: 28 · 2021: 38 · 2020: 41 · 2019: 28 · 2018: 40 · 2017: 29 · 2016: 24 · 2015: 13
FWCI: 25.77
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Annals of Neurology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (UH3-TR000967, R01AG034924)
BrightFocus Foundation
Alzheimer's Association
Falk Medical Research Trust
Topics: Health Sciences › Medicine › Physiology › 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: Alzheimer's disease, Fyn tyrosine kinase, AZD0530, Src family kinase inhibitor, amyloid-beta oligomers, Pyk2, NMDA receptor NR2B, APP/PS1 mice, spatial memory impairment, synaptic loss, PSD-95, microglial activation, tau phosphorylation, drug repurposing, disease-modifying therapy
MeSH terms: Alzheimer Disease, Animals, Behavior, Animal, Disease Models, Animal, Mice, Inbred C57BL, Mice, Transgenic, Quinazolines, Signal Transduction, Amyloid beta-Peptides, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-fyn, Mice, Focal Adhesion Kinase 2, Benzodioxoles

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F yn inhibition rescues established memory and synapse loss in A lzheimer mice

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