The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network
Overview
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
Verification
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?
SORLA deletion as well as AD-associated Y1816C, G511R, E270K and Y141C variants can promote endosomal enlargement and dysregulated trafficking of targets such as APP and GLUA1 in iPSC-derived neurons.
“SORLA deletion as well as AD-associated Y1816C, G511R, E270K and Y141C variants can promote endosomal enlargement (Knupp, Mishra et al. 2020, Hung, Tuck et al. 2021, Mishra, Knupp et al. 2023, Jensen, Raska et al. 2024) and dysregulated trafficking of targets such as APP and GLUA1 in iPSC-derived neurons (Mishra, Knupp et al. 2022).”
From SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain (2026) · cites this paper as Hung, Tuck et al. 2021
The Results section, “Complete loss of SORL1 results in early endosome enlargement and lysosome dysfunction” (page unavailable), reports enlarged early endosomes in heterozygous and homozygous SORL1-null iPSC-derived neurons. This supports the deletion portion of the endosomal-enlargement claim, but the cited paper does not establish that the four named variants cause enlargement. The trafficking clause is attributed to a different citation in the citing sentence. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLoss of SORLA causes endo-lysosomal defects in neurons, including in endosomal recycling, autophagy, and lysosome function, resulting in increased secretion of toxic Aβ species and impaired synaptic activity.
“Studies investigating the role of SORLA in ad pathogenesis have extensively focused on neurons and revealed that loss of SORLA causes endo‐lysosomal defects in neurons, specifically in endosomal recycling, autophagy, and lysosome function, ultimately resulting in increased secretion of toxic Aβ species and impaired synaptic activity in neurons (Andersen et al. 2022; Hung et al. 2021; Knupp et al.”
From The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia (2025) · cites this paper as Hung et al. 2021
The Discussion (page unavailable) reports disrupted endosomal trafficking in SORL1-deficient human neurons and, with complete loss, lysosome dysfunction and impaired autophagy. The Results report increased extracellular Aβ40 and Aβ42, but do not establish that these peptides caused impaired synaptic activity. The copy does not specifically demonstrate an endosomal-recycling defect or report impaired synaptic activity. (LLM, conf=0.87)
Experimental — accuracy not yet measuredDepletion of SORLA in neurons leads to enlarged early endosomes, impairments in endo-lysosomal trafficking, changes in gene expression, and impaired neuronal function.
“Recent work from our group and others has shown that depletion of SORLA in neurons leads to enlarged early endosomes, impairments in endo‐lysosomal trafficking, changes in gene expression, and impaired neuronal function (Hung et al. 2021; Knupp et al. 2020; Lee et al. 2023; Mishra et al. 2023, 2022).”
From The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia (2025) · cites this paper as Hung et al. 2021
The Results section on early endosome enlargement and lysosome dysfunction reports enlarged early endosomes after SORL1 loss and endosomal and lysosomal defects after complete loss, supporting those parts of the claim in human neurons. The passages found do not establish changes in gene expression or impaired neuronal function; the Results section on APP processing instead reports no difference in APP mRNA expression. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSORLA deletion results in endosomal and lysosomal defects in iPSC-derived neurons.
“Previous groups have reported that SORLA deletion results in endosomal (Knupp, Mishra et al. 2020, Hung, Tuck et al. 2021), as well as lysosomal defects (Hung, Tuck et al. 2021) in iPSC-derived neurons.”
From SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain (2026) · cites this paper as Hung, Tuck et al. 2021
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The Cellular Phase of Alzheimer’s Disease
De Strooper, B., & Karran, E. (2016) · Cell · doi:10.1016/j.cell.2015.12.056 · Cited by 1,990
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661
Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells
Israel, M. A., Yuan, S. H., Bardy, C., Reyna, S. M., Mu, Y., Herrera, C., Hefferan, M. P., Van Gorp, S., Nazor, K. L., Boscolo, F. S., et al. (2012) · Nature · doi:10.1038/nature10821 · Cited by 1,253
Common genetic variation drives molecular heterogeneity in human iPSCs
Kilpinen, H., Goncalves, A., Leha, A., Afzal, V., Alasoo, K., Ashford, S., Bala, S., Bensaddek, D., Casale, F. P., Culley, O. J., et al. (2017) · Nature · doi:10.1038/nature22403 · Cited by 586
Nixon, R. A. (2017) · The FASEB Journal · doi:10.1096/fj.201700359 · Cited by 400 · cited 2×
“…accumulation of APP protein fragments generated from the amyloidogenic pathway within endosomal compartments disrupts endolysosomal function and autophagy (Colacurcio et al., 2018; Jiang et al., 2016, 2019; Kwart et al., 2019; Lauritzen et al., 2016, 2019; Nixon, 2007, 2017; Nixon et al., 2005).”
BackgroundLauritzen, I., Pardossi-Piquard, R., Bourgeois, A., Pagnotta, S., Biferi, M.-G., Barkats, M., Lacor, P., Klein, W., Bauer, C., & Checler, F. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1577-6 · Cited by 219
Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99)
Jiang, Y., Sato, Y., Im, E., Berg, M., Bordi, M., Darji, S., Kumar, A., Mohan, P. S., Bandyopadhyay, U., Diaz, A., et al. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.0578-19.2019 · Cited by 166
Dodson, S. E., Andersen, O. M., Karmali, V., Fritz, J. J., Cheng, D., Peng, J., Levey, A. I., Willnow, T. E., & Lah, J. J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4582-08.2008 · Cited by 141
Whole‐exome sequencing in 20,197 persons for rare variants in Alzheimer's disease
Raghavan, N. S., Brickman, A. M., Andrews, H., Manly, J. J., Schupf, N., Lantigua, R., Wolock, C. J., Kamalakaran, S., Petrovski, S., Tosto, G., et al. (2018) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.582 · Cited by 141
Flagged first, then by citations
Research works printed but not linked: 35
- Andersen, 2005, Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein, Proc. Natl. Acad. Sci. USA, 102, 13461, 10.1073/pnas.0503689102 · DOI · Paper page
- Andersen, 2016, Risk factor SORL1: from genetic association to functional validation in Alzheimer’s disease, Acta Neuropathol., 132, 653, 10.1007/s00401-016-1615-4 · DOI · Paper page
- Bettens, 2008, SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population, Hum. Mutat., 29, 769, 10.1002/humu.20725 · DOI
- Bruntraeger, 2019, Editing the genome of human induced pluripotent stem cells using CRISPR/Cas9 ribonucleoprotein complexes, 153, 10.1007/978-1-4939-9170-9_11 · DOI
- Caglayan, 2012, Identification of Alzheimer disease risk genotype that predicts efficiency of SORL1 expression in the brain, Arch. Neurol., 69, 373, 10.1001/archneurol.2011.788 · DOI
- Caglayan, 2014, Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer’s disease mutation, Sci. Transl. Med., 6, 223ra20, 10.1126/scitranslmed.3007747 · DOI · Paper page
- Chen, 2000, 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes modified for extended conjugation and restricted bond rotations, J. Org. Chem., 65, 2900, 10.1021/jo991927o · DOI
- Colacurcio, 2018, Dysfunction of autophagy and endosomal-lysosomal pathways: Roles in pathogenesis of Down syndrome and Alzheimer’s Disease, Free Radic. Biol. Med., 114, 40, 10.1016/j.freeradbiomed.2017.10.001 · DOI · Paper page
- Das, 2016, Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway, Nat. Neurosci., 19, 55, 10.1038/nn.4188 · DOI
- Fjorback, 2012, Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing, J. Neurosci., 32, 1467, 10.1523/JNEUROSCI.2272-11.2012 · DOI · Paper page
- Glerup, 2013, SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRα1 and RET, Cell Rep., 3, 186, 10.1016/j.celrep.2012.12.011 · DOI · Paper page
- Gorvel, 1991, rab5 controls early endosome fusion in vitro, Cell, 64, 915, 10.1016/0092-8674(91)90316-Q · DOI
- Holstege, 2017, Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy, Eur. J. Hum. Genet., 25, 973, 10.1038/ejhg.2017.87 · DOI · Paper page
- Hung, 2018, Altered γ-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer’s Disease, Cell Rep., 25, 3647, 10.1016/j.celrep.2018.11.095 · DOI · Paper page
- Jiang, 2016, Partial BACE1 reduction in a Down syndrome mouse model blocks Alzheimer-related endosomal anomalies and cholinergic neurodegeneration: role of APP-CTF, Neurobiol. Aging, 39, 90, 10.1016/j.neurobiolaging.2015.11.013 · DOI · Paper page
- Karch, 2015, Alzheimer’s disease risk genes and mechanisms of disease pathogenesis, Biol. Psychiatry, 77, 43, 10.1016/j.biopsych.2014.05.006 · DOI · Paper page
- Kimura, 2009, SORL1 is genetically associated with Alzheimer disease in a Japanese population, Neurosci. Lett., 461, 177, 10.1016/j.neulet.2009.06.014 · DOI
- Klinger, 2011, SorLA regulates the activity of lipoprotein lipase by intracellular trafficking, J. Cell Sci., 124, 1095, 10.1242/jcs.072538 · DOI
- Knupp, 2020, Depletion of the AD risk gene SORL1 selectively impairs neuronal endosomal traffic independent of amyloidogenic APP processing, Cell Rep., 31, 107719, 10.1016/j.celrep.2020.107719 · DOI · Paper page
- Kwart, 2019, A large panel of isogenic APP and PSEN1 mutant human iPSC neurons reveals shared endosomal abnormalities Mediated by APP β-CTFs, not Aβ, Neuron, 104, 256, 10.1016/j.neuron.2019.07.010 · DOI
- Lauritzen, 2019, Does Intraneuronal Accumulation of Carboxyl-terminal Fragments of the Amyloid Precursor Protein Trigger Early Neurotoxicity in Alzheimer’s Disease?, Curr. Alzheimer Res., 16, 453, 10.2174/1567205016666190325092841 · DOI
- Mehmedbasic, 2015, SorLA complement-type repeat domains protect the amyloid precursor protein against processing, J. Biol. Chem., 290, 3359, 10.1074/jbc.M114.619940 · DOI
- Nicolas, 2016, SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease, Mol. Psychiatry, 21, 831, 10.1038/mp.2015.121 · DOI · Paper page
- Nixon, 2007, Autophagy, amyloidogenesis and Alzheimer disease, J. Cell Sci., 120, 4081, 10.1242/jcs.019265 · DOI · Paper page
- Nixon, 2005, Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study, J. Neuropathol. Exp. Neurol., 64, 113, 10.1093/jnen/64.2.113 · DOI · Paper page
- O’Brien, 2011, Amyloid precursor protein processing and Alzheimer’s disease, Annu. Rev. Neurosci., 34, 185, 10.1146/annurev-neuro-061010-113613 · DOI · Paper page
- Rogaeva, 2007, The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease, Nat. Genet., 39, 168, 10.1038/ng1943 · DOI · Paper page
- Rubinsztein, 2009, In search of an “autophagomometer.”, Autophagy, 5, 585, 10.4161/auto.5.5.8823 · DOI · Paper page
- Sager, 2007, Neuronal LR11/sorLA expression is reduced in mild cognitive impairment, Ann. Neurol., 62, 640, 10.1002/ana.21190 · DOI · Paper page
- Scherzer, 2004, Loss of apolipoprotein E receptor LR11 in Alzheimer disease, Arch. Neurol., 61, 1200, 10.1001/archneur.61.8.1200 · DOI · Paper page
- Shi, 2012, Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks, Nat. Protoc., 7, 1836, 10.1038/nprot.2012.116 · DOI · Paper page
- Simonsen, 1998, EEA1 links PI(3)K function to Rab5 regulation of endosome fusion, Nature, 394, 494, 10.1038/28879 · DOI · Paper page
- Tan, 2009, SORL1 haplotypes modulate risk of Alzheimer’s disease in Chinese, Neurobiol. Aging, 30, 1048, 10.1016/j.neurobiolaging.2007.10.013 · DOI
- Verheijen, 2016, A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease, Acta Neuropathol., 132, 213, 10.1007/s00401-016-1566-9 · DOI · Paper page
- Young, 2015, Elucidating molecular phenotypes caused by the SORL1 Alzheimer’s disease genetic risk factor using human induced pluripotent stem cells, Cell Stem Cell, 16, 373, 10.1016/j.stem.2015.02.004 · DOI
Cited by
Sorted by citations
The contribution of altered neuronal autophagy to neurodegeneration
Filippone, A., Esposito, E., Mannino, D., Lyssenko, N., & Praticò, D. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108178 · Cited by 55
The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia
Mishra, S., Morshed, N., Sidhu, S. B., Kinoshita, C., Stevens, B., Jayadev, S., & Young, J. E. (2025) · Glia · doi:10.1002/glia.70009 · Cited by 31
Thirumalai, S., Livesey, F. J., Patani, R., & Hung, C. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.14560 · Cited by 9
Self-citationSORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain
Huang, H., Shi, C. H., Yang, W., Piña-Crespo, J. C., Bhatnagar, J., Curatolo, J., Murad, R., Shah, P., Campos, A., Houser, A., et al. (2026) · Science Advances · doi:10.1126/sciadv.aed6825 · Cited by 1
Metadata
- Authors
- Hung, C., Tuck, E., Stubbs, V., van der Lee, S. J., Aalfs, C., van Spaendonk, R., Scheltens, P., Hardy, J., Holstege, H., & Livesey, F. J.
- ORCID
- Scheltens, Philip
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2021-06
- Volume
- 35
- Issue
- 11
- Pages
- 109259
- ISSN
- 2211-1247
- PMC
- PMC8220253
- Cited by
- 98
- References
- 9
- Language
- en
- Licence
- Funders
- Alzheimer's Research Trust (ARUK-RADF2019A-007)
- Medical Research Council (MR/N026004/1, 202903/Z/16/Z)
- European Commission (JPND2019-466-197)
- NIHR Great Ormond Street Hospital Biomedical Research Centre
- UK Dementia Research Institute
- Health~Holland
- UCLH Biomedical Research Centre
- Alzheimer's Society
- ZonMw (733051110)
- Wellcome Trust (WT101052MA)
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
