Aberrant synaptic PTEN in symptomatic Alzheimer's patients may link synaptic depression to network failure
Open accessAbstract
In Alzheimer's disease (AD), Amyloid β (Aβ) impairs synaptic function by inhibiting long-term potentiation (LTP), and by facilitating long-term depression (LTD). There is now evidence from AD models that Aβ provokes this shift toward synaptic depression by triggering the access to and accumulation of PTEN in the postsynaptic terminal of hippocampal neurons. Here we quantified the PTEN in 196,138 individual excitatory dentate gyrus synapses from AD patients at different stages of the disease and from controls with no neuropathological findings. We detected a gradual increase of synaptic PTEN in AD brains as the disease progresses, in conjunction with a significant decrease in synaptic density. The synapses that remain in symptomatic AD patients are more likely to be smaller and exhibit fewer AMPA receptors (AMPARs). Hence, a high Aβ load appears to strongly compromise human hippocampal synapses, as reflected by an increase in PTEN, inducing a loss of AMPARs that may eventually provoke synaptic failure and loss.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the AD brain, Aβ recruits PTEN protein into neuronal synapses, which drives synaptic depression.
“In the AD brain, Aβ recruits PTEN protein into neuronal synapses, which drives synaptic depression. 62”
From Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations (2026) · cites this paper as [62]
The Discussion (page not supplied) describes Aβ-driven PTEN recruitment and synaptic depression as a proposed mechanism supported by cellular AD models. In human AD brains, the paper finds increased synaptic PTEN associated with synaptic changes, but does not establish that Aβ causes PTEN recruitment or that PTEN drives depression there. The claim states that causal sequence in the AD brain more firmly than the source does. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Alzheimer's Disease Is a Synaptic Failure
Selkoe, D. J. (2002) · Science · doi:10.1126/science.1074069 · Cited by 4,420 · see citing works
Braak, H., Alafuzoff, I., Arzberger, T., Kretzschmar, H., & Del Tredici, K. (2006) · Acta Neuropathologica · doi:10.1007/s00401-006-0127-z · Cited by 3,172 · see citing works
Intracellular amyloid-β in Alzheimer's disease
LaFerla, F. M., Green, K. N., & Oddo, S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2168 · Cited by 1,942 · see citing works
Amyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks
Palop, J. J., & Mucke, L. (2010) · Nature Neuroscience · doi:10.1038/nn.2583 · Cited by 1,651 · see citing works
Pattern separation in the hippocampus
Yassa, M. A., & Stark, C. E. L. (2011) · Trends in Neurosciences · doi:10.1016/j.tins.2011.06.006 · Cited by 1,544 · see citing works
AMPAR Removal Underlies Aβ-Induced Synaptic Depression and Dendritic Spine Loss
Hsieh, H., Boehm, J., Sato, C., Iwatsubo, T., Tomita, T., Sisodia, S., & Malinow, R. (2006) · Neuron · doi:10.1016/j.neuron.2006.10.035 · Cited by 1,042 · see citing works
Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses
Zhou, Q., Homma, K. J., & Poo, M.-M. (2004) · Neuron · doi:10.1016/j.neuron.2004.11.011 · Cited by 1,025 · see citing works
Differential Control of Learning and Anxiety along the Dorsoventral Axis of the Dentate Gyrus
Kheirbek, M. A., Drew, L. J., Burghardt, N. S., Costantini, D. O., Tannenholz, L., Ahmari, S. E., Zeng, H., Fenton, A. A., & Hen, R. (2013) · Neuron · doi:10.1016/j.neuron.2012.12.038 · Cited by 713 · see citing works
Alzheimer's disease drug development pipeline: 2018
Cummings, J., Lee, G., Ritter, A., & Zhong, K. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.03.009 · Cited by 697 · see citing works
Dentate gyrus circuits for encoding, retrieval and discrimination of episodic memories
Hainmueller, T., & Bartos, M. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0260-z · Cited by 474 · see citing works
Age-related memory deficits linked to circuit-specific disruptions in the hippocampus
Yassa, M. A., Mattfeld, A. T., Stark, S. M., & Stark, C. E. L. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1101567108 · Cited by 436 · see citing works
D'Andrea, M. R., Nagele, R. G., Wang, H., Peterson, P. A., & Lee, D. H. S. (2001) · Histopathology · doi:10.1046/j.1365-2559.2001.01082.x · Cited by 390 · see citing works
Facilitation of AMPA Receptor Synaptic Delivery as a Molecular Mechanism for Cognitive Enhancement
Knafo, S., Venero, C., Sánchez‐Puelles, C., Pereda-Pérez, I., Franco, A. C. G., Sandi, C., Suárez, L. M., Solís, J. M., Alonso‐Nanclares, L., Martín, E. D., et al. (2012) · PLoS Biology · doi:10.1371/journal.pbio.1001262 · Cited by 310 · see citing works
Self-citationReactivation of Neural Ensembles during the Retrieval of Recent and Remote Memory
Tayler, K. K., Tanaka, K. Z., Reijmers, L. G. J. E., & Wiltgen, B. J. (2012) · Current Biology · doi:10.1016/j.cub.2012.11.019 · Cited by 296 · see citing works
Lee, I., & Kesner, R. P. (2004) · Hippocampus · doi:10.1002/hipo.10167 · Cited by 253 · see citing works
AMPA receptor downscaling at the onset of Alzheimer's disease pathology in double knockin mice
Chang, E. H., Savage, M. J., Flood, D. G., Thomas, J. M., Levy, R. B., Mahadomrongkul, V., Shirao, T., Aoki, C., & Huerta, P. T. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507313103 · Cited by 225 · see citing works
Challenges for Alzheimer's Disease Therapy: Insights from Novel Mechanisms Beyond Memory Defects
Frozza, R. L., Lourenco, M. V., & Felice, F. G. D. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00037 · Cited by 202 · see citing works
Gu, Z., Liu, W., & Yan, Z. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m806508200 · Cited by 178 · see citing works
State-dependent Ras signaling and AMPA receptor traffickingPreprint
Qin, Y., Zhu, Y., Baumgart, J. P., Stornetta, R. L., Seidenman, K. J., Mack, V., Aelst, L. V., & Zhu, J. (2005) · Genes & Development · doi:10.1101/gad.342205 · Cited by 177 · see citing works
Bayer, T. A., Wirths, O., Majtényi, K., Hartmann, T., Multhaup, G., Beyreuther, K. T., & Czech, C. (2001) · Brain Pathology · doi:10.1111/j.1750-3639.2001.tb00376.x · Cited by 172 · see citing works
LaFerla, F. M., Troncoso, J. C., Strickland, D. K., Kawas, C. H., & Jay, G. D. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119536 · Cited by 162 · see citing works
PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane
Arendt, K. L., Royo, M., Fernández‐Monreal, M., Knafo, S., Petrok, C. N., Martens, J. R., & Esteban, J. A. (2009) · Nature Neuroscience · doi:10.1038/nn.2462 · Cited by 158 · see citing works
Self-citationPTEN recruitment controls synaptic and cognitive function in Alzheimer's models
Knafo, S., Sánchez‐Puelles, C., Palomer, E., Delgado, I., Draffin, J. E., Mingo, J., Wahle, T., Kaleka, K. S., Mou, L., Pereda-Pérez, I., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4225 · Cited by 147 · see citing works
Self-citationPTEN is recruited to the postsynaptic terminal for NMDA receptor‐dependent long‐term depression
Jurado, S., Benoist, M., Lario, A., Knafo, S., Petrok, C. N., & Esteban, J. A. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.160 · Cited by 146 · see citing works
Self-citationSpines, plasticity, and cognition in Alzheimer's model mice
Spires-Jones, T., & Knafo, S. (2012) · Neural Plasticity · doi:10.1155/2012/319836 · Cited by 133 · see citing works
Self-citationWidespread Changes in Dendritic Spines in a Model of Alzheimer's Disease
Knafo, S., Alonso-Nanclares, L., Gonzalez-Soriano, J., Merino-Serrais, P., Fernaud-Espinosa, I., Ferrer, I., & DeFelipe, J. (2009) · Cerebral Cortex · doi:10.1093/cercor/bhn111 · Cited by 132 · see citing works
Self-citationAmyloid-β effects on synapses and memory require AMPA receptor subunit GluA3
Reinders, N. R., Pao, Y., Renner, M., Matos, C. D. S., Lodder, T. R., Malinow, R., & Kessels, H. W. H. G. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1614249113 · Cited by 126 · see citing works
Takeuchi, K., Gertner, M. J., Zhou, J., Parada, L. F., Bennett, M. V. L., & Zukin, R. S. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1222803110 · Cited by 119 · see citing works
LTD-like molecular pathways in developmental synaptic pruning
Piochon, C., Kano, M., & Hansel, C. (2016) · Nature Neuroscience · doi:10.1038/nn.4389 · Cited by 108 · see citing works
Sperow, M., Berry, R. B., Bayazitov, I. T., Zhu, G. G., Baker, S. J., & Zakharenko, S. S. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.220236 · Cited by 101 · see citing works
Transcranial magnetic stimulation predicts cognitive decline in patients with Alzheimer’s disease
Motta, C., Lorenzo, F. D., Ponzo, V., Pellicciari, M. C., Bonnı̀, S., Picazio, S., Mercuri, N. B., Caltagirone, C., Martorana, A., & Koch, G. (2018) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2017-317879 · Cited by 91 · see citing works
Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells
Madroñal, N., Delgado-Garcia, J. M., Fernández-Guizán, A., Chatterjee, J., Köhn, M., Mattucci, C., Jain, A., Tsetsenis, T., Illarionova, A., Grinevich, V., et al. (2016) · Nature Communications · doi:10.1038/ncomms10923 · Cited by 88 · see citing works
Montero‐Crespo, M., Domínguez-Álvaro, M., Alonso‐Nanclares, L., DeFelipe, J., & Blázquez‐Llorca, L. (2020) · Brain · doi:10.1093/brain/awaa406 · Cited by 88 · see citing works
Hobert, J. A., Embacher, R. A., Mester, J. L., Frazier, T. W., & Eng, C. (2013) · European Journal of Human Genetics · doi:10.1038/ejhg.2013.114 · Cited by 84 · see citing works
Cummings, D. M., Liu, W., Portelius, E., Bayram, S., Yasvoina, M. V., Ho, H., Smits, H., Ali, S. S., Steinberg, R., Pegasiou, C.-M., et al. (2015) · Brain · doi:10.1093/brain/awv127 · Cited by 81 · see citing works
PTEN: Local and Global Modulation of Neuronal Function in Health and Disease
Knafo, S., & Esteban, J. A. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2016.11.008 · Cited by 79 · see citing works
Self-citationSabbagh, M. N., Hendrix, S. B., & Harrison, J. (2018) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.11.004 · Cited by 79 · see citing works
The dentate gyrus in Alzheimer's disease
Ohm, T. G. (2007) · Progress in brain research · doi:10.1016/s0079-6123(07)63039-8 · Cited by 78 · see citing works
Knafo, S., Venero, C., Merino‐Serrais, P., Fernaud-Espinosa, I., González‐Soriano, J., Ferrer, I., Santpere, G., & DeFelipe, J. (2009) · The Journal of Pathology · doi:10.1002/path.2565 · Cited by 73 · see citing works
Self-citationPreferential Targeting of Lateral Entorhinal Inputs onto Newly Integrated Granule Cells
Woods, N. I., Vaaga, C. E., Chatzi, C. A., Adelson, J. D., Collie, M. F., Perederiy, J. V., Tovar, K. R., & Westbrook, G. L. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.1737-17.2018 · Cited by 62 · see citing works
Layer‐specific alterations to CA1 dendritic spines in a mouse model of Alzheimer's disease
Merino‐Serrais, P., Knafo, S., Alonso‐Nanclares, L., Fernaud-Espinosa, I., & DeFelipe, J. (2010) · Hippocampus · doi:10.1002/hipo.20861 · Cited by 49 · see citing works
Self-citationThe PTEN Phosphatase is Essential for Long-Term Depression of Hippocampal Synapses
Wang, Y., Cheng, A., & Mattson, M. P. (2006) · NeuroMolecular Medicine · doi:10.1385/nmm:8:3:329 · Cited by 44 · see citing works
Persistent Synapse Loss Induced by Repetitive LTD in Developing Rat Hippocampal Neurons
Shinoda, Y., Tanaka, T., Tominaga‐Yoshino, K., & Ogura, A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010390 · Cited by 42 · see citing works
PTENα Modulates CaMKII Signaling and Controls Contextual Fear Memory and Spatial Learning
Wang, P., Mei, F., Hu, J., Zhu, M., Qi, H., Chen, X., Li, R., McNutt, M. A., & Yin, Y. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.05.088 · Cited by 26 · see citing works
Sánchez‐Puelles, C., Calleja-Felipe, M., Ouro, A., Bougamra, G., Arroyo, A., Diez, I. P., Erramuzpe, A., Cortés, J. M., Hernández, J. M., Luján, R., et al. (2019) · Cerebral Cortex · doi:10.1093/cercor/bhz103 · Cited by 26 · see citing works
Self-citationPTEN regulates AMPA receptor-mediated cell viability in iPS-derived motor neurons
Yang, D., Wang, X.-L., Ismail, A., Ashman, C. J., Valori, C. F., Wang, G., Gao, S., Higginbottom, A., Ince, P. G., Azzouz, M., et al. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.55 · Cited by 25 · see citing works
Amyloid‐β oligomers suppress subunit‐specific glutamate receptor increase during LTP
Tanaka, H., Sakaguchi, D., & Hirano, T. (2019) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2019.10.003 · Cited by 19 · see citing works
Noroozıan, M. (2015) · Neurologic Clinics · doi:10.1016/j.ncl.2015.08.005 · Cited by 16 · see citing works
Lalatsa, A., Sun, Y., Gamboa, J. I., & Knafo, S. (2020) · Pharmaceutical Research · doi:10.1007/s11095-020-02915-8 · Cited by 12 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Verma, A., Shteinfer‐Kuzmine, A., Kamenetsky, N., Pittala, S., Paul, A., Crystal, E. N., Ouro, A., Caspi, V. C., Pandey, S. K., Monsonego, A., et al. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00329-7 · Cited by 106 · see citing works
Self-citationThe glutamatergic system in Alzheimer’s disease: a systematic review with meta-analysis
Soares, C., Ros, L. U. D., Machado, L. S., da Rocha, A. S., Lazzarotto, G., Carello‐Collar, G., Bastiani, M. A. D., Ferrari‐Souza, J. P., Lussier, F. Z., Souza, D. O., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02473-0 · Cited by 47 · see citing works
Sandau, U. S., McFarland, T. J., Smith, S. J., Galasko, D. R., Quinn, J. F., & Saugstad, J. A. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.864022 · Cited by 46 · see citing works
Zhao, M., Tanourlouee, S. B., McCracken, S., & Williams, P. R. (2025) · Neurophotonics · doi:10.1117/1.nph.12.s2.s22805 · Cited by 9 · see citing works
Neuronal insulin signaling and resistance: a balancing act of kinases and phosphatases
Sharma, M., Yadav, Y., & Dey, C. S. (2023) · Journal of Endocrinology · doi:10.1530/joe-23-0151 · Cited by 9 · see citing works
Jung, M., Jung, J., Pfeifer, J., Hartmann, C., Ehrhardt, T., Abid, C. L., Kintzel, J., Puls, A., Santos, A. N., Hollemann, T., et al. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03633-z · Cited by 9 · see citing works
Moreira, N. C. D. S., Piassi, L. D. O., Lima, J. E. B. D. F., Passos, G., & Sakamoto-Hojo, E. (2025) · Journal of Alzheimer's Disease · doi:10.1177/13872877251352194 · Cited by 5 · see citing works
Nordbeck, A. J., Martá‐Ariza, M., Ek Olofsson, H., Kanshin, E., Ueberheide, B., Jones, K., Sanford, B., Hamlett, E. D., Head, E., Mufson, E. J., et al. (2026) · Alzheimer's & Dementia · doi:10.1002/alz.71776
“62 It is therefore possible that PTEN pathway abnormalities contribute to the overactivation of the PI3K/AKT/mTOR signaling pathway in DS-AD as well.”
Rasadi, A., Sasani, S. T., & Ajamian, F. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05159-y
Sánchez-Thomas, R., Bautista-Perez, S. M., Santana-Martínez, R. A., Silva‐Islas, C. A., Figueroa, A., Barrera‐Oviedo, D., & Maldonado, P. D. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-44173-8.00015-2
Alzheimer’s Disease (AD) as a Synaptic Failure
Knafo, S. (2026) · Oxford Research Encyclopedia of Neuroscience · doi:10.1093/9780197851494.003.0581
Self-citationSingh, R., Paliwal, T., Joshi, R., Paliwal, V., Dubey, P., Bhardwaj, S., Jain, S., Paliwal, S., & Sharma, S. (2026) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2026.154524
- Authors
- Díaz González, M., Buberman, A., Morales, M., Ferrer, I., & Knafo, S.
- Affiliations
- Ben-Gurion University of the Negev (IL)
- University of the Basque Country (ES)
- Ikerbasque (ES)
- Corresponding author
- Knafo, Shira
- Venue
- Frontiers in Synaptic Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2021-05-11
- Volume
- 13
- Pages
- 683290-683290
- ISSN
- 1663-3563 (ISSN-L)
- PMC
- PMC8144462
- OpenAlex
- W3162156382
- Cited by
- 12
- References
- 49
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 2
- FWCI
- 0.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Synaptic Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Communities in ADDI (Universidad del Pais Vasco) (submittedVersion, cc-by)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Hispana (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, PTEN, amyloid-beta, synaptic depression, long-term depression, long-term potentiation, AMPA receptors, hippocampus, dentate gyrus, synaptic density, synaptic failure, synaptic loss, disease progression
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
