Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer’s disease and aged brains: increased levels correlate with neuropathology
Open accessAbstract
Progranulin (PGRN) is a protein encoded by the GRN gene with multiple identified functions including as a neurotrophic factor, tumorigenic growth factor, anti-inflammatory cytokine and regulator of lysosomal function. A single mutation in the human GRN gene resulting in reduced PGRN expression causes types of frontotemporal lobar degeneration resulting in frontotemporal dementia. Prosaposin (PSAP) is also a multifunctional neuroprotective secreted protein and regulator of lysosomal function. Interactions of PGRN and PSAP affect their functional properties. Their roles in Alzheimer's disease (AD), the leading cause of dementia, have not been defined. In this report, we examined in detail the cellular expression of PGRN in middle temporal gyrus samples of a series of human brain cases (n = 45) staged for increasing plaque pathology. Immunohistochemistry showed PGRN expression in cortical neurons, microglia, cerebral vessels and amyloid beta (Aβ) plaques, while PSAP expression was mainly detected in neurons and Aβ plaques, and to a limited extent in astrocytes. We showed that there were increased levels of PGRN protein in AD cases and corresponding increased levels of PSAP. Levels of PGRN and PSAP protein positively correlated with amyloid beta (Aβ), with PGRN levels correlating with phosphorylated tau (serine 205) levels in these samples. Although PGRN colocalized with lysosomal-associated membrane protein-1 in neurons, most PGRN associated with Aβ plaques did not. Aβ plaques with PGRN and PSAP deposits were identified in the low plaque non-demented cases suggesting this was an early event in plaque formation. We did not observe PGRN-positive neurofibrillary tangles. Co-immunoprecipitation studies of PGRN from brain samples identified only PSAP associated with PGRN, not sortilin or other known PGRN-binding proteins, under conditions used. Most PGRN associated with Aβ plaques were immunoreactive for PSAP showing a high degree of colocalization of these proteins that did not change between disease groups. As PGRN supplementation has been considered as a therapeutic approach for AD, the possible involvement of PGRN and PSAP interactions in AD pathology needs to be further considered.
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 astrocytes, PSAP promotes motility and neuroprotective function, and is upregulated in the brains of patients with AD.
“In astrocytes, it promotes motility and neuroprotective function, and is upregulated in the brains of patients with AD. 47 , 48”
From Loss of <i>Inpp5d</i> has disease‐relevant and sex‐specific effects on glial transcriptomes (2024) · cites this paper as [48]
The Results report increased PSAP protein in AD brain samples, and the Introduction describes PSAP as having neuroprotective properties. However, the paper does not report that PSAP promotes astrocyte motility or establish a neuroprotective function specifically in astrocytes; the Results find only limited PSAP staining in those cells. The indexed passages provide section labels but no page numbers. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPSAP is involved in the regulation of lysosomes.
“Moreover, these data also revealed decreased expression of the genes encoding APP and PSAP (prosaposin), the latter of which is involved in the regulation of lysosomes. 19”
From The MR1/MAIT cell axis enhances dystrophic neurite development in Alzheimer's disease (2025) · cites this paper as [19]
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
NIH Image to ImageJ: 25 years of image analysis
Schneider, C. A., Rasband, W. S., & Eliceiri, K. W. (2012) · Nature Methods · doi:10.1038/nmeth.2089 · Cited by 64,638 · see citing works
Diagnosis and management of dementia with Lewy bodies: Third report of the DLB consortium
McKeith, I. G., Dickson, D. W., Lowe, J., Emre, M., O'Brien, J. T., Feldman, H., Cummings, J., Duda, J. E., Lippa, C., Perry, E. K., et al. (2005) · Neurology · doi:10.1212/01.wnl.0000187889.17253.b1 · Cited by 5,069 · see citing works
The neuropathological diagnosis of Alzheimer's disease
DeTure, M. A., & Dickson, D. W. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0333-5 · Cited by 3,329 · cited 1× · see citing works
“affected subjects show accumulations of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFT), the hallmark pathological features of this disease [2].”
BackgroundThe antibody aducanumab reduces Aβ plaques in Alzheimer’s disease
Sevigny, J., Chiao, P., Bussière, T., Weinreb, P. H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., et al. (2016) · Nature · doi:10.1038/nature19323 · Cited by 3,059 · see citing works
Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.
Hixson, J., & Vernier, D. (1990) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)43176-1 · Cited by 2,933 · see citing works
Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17
Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., et al. (2006) · Nature · doi:10.1038/nature05016 · Cited by 2,058 · see citing works
Lui, H., Zhang, J., Makinson, S. R., Cahill, M. K., Kelley, K. W., Huang, H.-Y., Shang, Y., Oldham, M. C., Martens, L. H., Gao, F., et al. (2016) · Cell · doi:10.1016/j.cell.2016.04.001 · Cited by 729 · see citing works
the Arizona Parkinson’s Disease Consortium, Beach, T. G., Adler, C. H., Lue, L., Sue, L. I., Bachalakuri, J., Henry-Watson, J., Sasse, J., Boyer, S., Shirohi, S., et al. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0538-8 · Cited by 698 · see citing works
Self-citationSortilin-Mediated Endocytosis Determines Levels of the Frontotemporal Dementia Protein, Progranulin
Hu, F., Padukkavidana, T., Vægter, C. B., Brady, O. A., Zheng, Y., Mackenzie, I. R., Feldman, H., Nykjær, A., & Strittmatter, S. M. (2010) · Neuron · doi:10.1016/j.neuron.2010.09.034 · Cited by 545 · see citing works
Beach, T. G., Adler, C. H., Sue, L. I., Serrano, G., Shill, H. A., Walker, D. G., Lue, L., Roher, A. E., Dugger, B. N., Maarouf, C., et al. (2015) · Neuropathology · doi:10.1111/neup.12189 · Cited by 460 · see citing works
Self-citationDamme, P. V., Hoecke, A. V., Lambrechts, D., Vanacker, P., Bogaert, E., Swieten, J. C. V., Carmeliet, P., Bosch, L. V. D., & Robberecht, W. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200712039 · Cited by 421 · see citing works
Gowrishankar, S., Yuan, P., Wu, Y., Schrag, M., Paradise, S., Grutzendler, J., De Camilli, P., & Ferguson, S. M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1510329112 · Cited by 406 · see citing works
Cellular Localization of Gene Expression for Progranulin
DANIEL, R. L., He, Z., Carmichael, K. P., Halper, J. T., & Bateman, A. (2000) · Journal of Histochemistry & Cytochemistry · doi:10.1177/002215540004800713 · Cited by 346 · see citing works
Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury
Martens, L. H., Zhang, J., Barmada, S. J., Zhou, P., Kamiya, S., Sun, B., Min, S.-W., Gan, L., Finkbeiner, S. M., Huang, E. J., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63113 · Cited by 313 · see citing works
Stauffer, W. T., Sheng, H., & Lim, H. N. (2018) · Scientific Reports · doi:10.1038/s41598-018-33592-8 · Cited by 299 · see citing works
The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene
Mackenzie, I. R., Baker, M., Pickering-Brown, S. M., Hsiung, G. R., Lindholm, C., Dwosh, E., Gass, J. M., Cannon, A. D., Rademakers, R., Hutton, M., et al. (2006) · Brain · doi:10.1093/brain/awl271 · Cited by 294 · see citing works
Newell, K. L., Hyman, B. T., Growdon, J. H., & Hedley-Whyte, E. T. (1999) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199911000-00004 · Cited by 289 · see citing works
Finch, N., Carrasquillo, M. M., Baker, M., Rutherford, N. J., Coppola, G., DeJesus-Hernandez, M., Crook, R., Hunter, T., Ghidoni, R., Benussi, L., et al. (2011) · Neurology · doi:10.1212/wnl.0b013e31820a0e3b · Cited by 243 · see citing works
Self-citationProgranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models
Minami, S. S., Min, S.-W., Krabbe, G., Wang, C., Zhou, Y., Asgarov, R., Li, Y., Martens, L. H., Elia, L. P., Ward, M. E., et al. (2014) · Nature Medicine · doi:10.1038/nm.3672 · Cited by 237 · see citing works
The lysosomal function of progranulin, a guardian against neurodegeneration
Paushter, D. H., Du, H., Feng, T., & Hu, F. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1861-8 · Cited by 230 · see citing works
Progranulin in frontotemporal lobar degeneration and neuroinflammation
Ahmed, Z., Mackenzie, I. R., Hutton, M. L., & Dickson, D. W. (2007) · Journal of Neuroinflammation · doi:10.1186/1742-2094-4-7 · Cited by 220 · see citing works
Granulins, a novel class of peptide from leukocytes
Bateman, A., Belcourt, D., Bennett, H. P. J., Lazure, C., & Solomon, S. (1990) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(05)80908-8 · Cited by 206 · see citing works
Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin
Zhou, X., Sun, L., de Oliveira, F. M. B., Qi, X., Brown, W. J., Smolka, M. B., Sun, Y., & Hu, F. (2015) · The Journal of Cell Biology · doi:10.1083/jcb.201502029 · Cited by 201 · see citing works
Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis
Ward, M. E., Chen, R., Huang, H.-Y., Ludwig, C., Telpoukhovskaia, M., Taubes, A., Boudin, H., Minami, S. S., Reichert, M., Albrecht, P., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aah5642 · Cited by 193 · see citing works
Yin, F., Dumont, M., Banerjee, R., Ma, Y., Li, H., Lin, M. T., Beal, M. F., Nathan, C., Thomas, B., & Ding, A. (2010) · The FASEB Journal · doi:10.1096/fj.10-161471 · Cited by 180 · see citing works
Granulin Is a Soluble Cofactor for Toll-like Receptor 9 Signaling
Park, B., Buti, L., Lee, S., Matsuwaki, T., Spooner, E., Brinkmann, M. M., Nishihara, M., & Ploegh, H. L. (2011) · Immunity · doi:10.1016/j.immuni.2011.01.018 · Cited by 176 · see citing works
Filiano, A. J., Martens, L. H., Young, A. H., Warmus, B. A., Zhou, P., Diaz‐Ramirez, G., Jiao, J., Zhang, Z., Huang, E. J., Gao, F., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.6103-11.2013 · Cited by 172 · see citing works
Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes
Tanaka, Y., Suzuki, G., Matsuwaki, T., Hosokawa, M., Serrano, G. E., Beach, T. G., Yamanouchi, K., Hasegawa, M., & Nishihara, M. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx011 · Cited by 172 · see citing works
Self-citationProgranulin regulates neuronal outgrowth independent of Sortilin
Gass, J. M., Lee, C. W., Cook, C. N., Finch, N. A., Stetler, C. T., Jansen‐West, K. R., Lewis, J. M., Link, C. D., Rademakers, R., Nykjær, A., et al. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-33 · Cited by 157 · see citing works
Improved Immunodetection of Endogenous α-Synuclein
Lee, B. R., & Kamitani, T. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023939 · Cited by 155 · see citing works
Tanaka, Y., CHAMBERS, J. K., Matsuwaki, T., Yamanouchi, K., & Nishihara, M. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0078-x · Cited by 155 · see citing works
Tanaka, Y., Matsuwaki, T., Yamanouchi, K., & Nishihara, M. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.06.049 · Cited by 153 · see citing works
Arrant, A. E., Onyilo, V. C., Unger, D. E., & Roberson, E. D. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.3081-17.2018 · Cited by 152 · see citing works
Progranulin functions as a cathepsin D chaperone to stimulate axonal outgrowth in vivo
Beel, S., Moisse, M., Damme, M., De Muynck, L., Robberecht, W., Van Den Bosch, L., Saftig, P., & Van Damme, P. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx162 · Cited by 146 · see citing works
The protective role of prosaposin and its receptors in the nervous system
Meyer, R. C., Giddens, M. M., Coleman, B. M., & Hall, R. A. (2014) · Brain Research · doi:10.1016/j.brainres.2014.08.022 · Cited by 142 · see citing works
The neuropathology and clinical phenotype of FTD with progranulin mutations
Mackenzie, I. R. (2007) · Acta Neuropathologica · doi:10.1007/s00401-007-0223-8 · Cited by 140 · see citing works
Holler, C. J., Taylor, G., Deng, Q., & Kukar, T. L. (2017) · eNeuro · doi:10.1523/eneuro.0100-17.2017 · Cited by 133 · see citing works
EphA2 is a functional receptor for the growth factor progranulin
Neill, T., Buraschi, S., Goyal, A. K., Sharpe, C., Natkanski, E., Schaefer, L., Morrione, A., & Iozzo, R. V. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201603079 · Cited by 129 · see citing works
Zhou, X., Sun, L., Bracko, O., Choi, J. W., Jia, Y., Nana, A. L., Brady, O. A., Hernández, J. C. C., Nishimura, N., Seeley, W. W., et al. (2017) · Nature Communications · doi:10.1038/ncomms15277 · Cited by 127 · see citing works
Suárez‐Calvet, M., Capell, A., Araque Caballero, M. Á., Morenas‐Rodríguez, E., Fellerer, K., Franzmeier, N., Kleinberger, G., Eren, E., Deming, Y., Piccio, L., et al. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201809712 · Cited by 109 · see citing works
Zheng, Y., Brady, O. A., Meng, P. S., Mao, Y., & Hu, F. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021023 · Cited by 105 · see citing works
Liu, B., Mosienko, V., Vaccari Cardoso, B., Prokudina, D., Huentelman, M., Teschemacher, A. G., & Kasparov, S. (2018) · Glia · doi:10.1002/glia.23480 · Cited by 96 · see citing works
Walker, D. G., Whetzel, A. M., Serrano, G., Sue, L. I., Beach, T. G., & Lue, L.-F. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.09.023 · Cited by 93 · see citing works
Self-citationMo, J., Li, J., Yang, Z., Liu, Z., & Feng, J. (2017) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.469 · Cited by 92 · see citing works
Götzl, J. K., Colombo, A.-V., Fellerer, K., Reifschneider, A., Werner, G., Tahirović, S., Haass, C., & Capell, A. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0281-5 · Cited by 92 · see citing works
Bossù, P., Salani, F., Alberici, A., Archetti, S., Bellelli, G., Galimberti, D., Scarpini, E. A., Spalletta, G., Caltagirone, C., Padovani, A., et al. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-65 · Cited by 91 · see citing works
Prosaposin is a regulator of progranulin levels and oligomerization
Nicholson, A. M., Finch, N. A., Almeida, M., Perkerson, R. B., van Blitterswijk, M., Wojtas, A., Cenik, B., Rotondo, S., Inskeep, V., Almasy, L., et al. (2016) · Nature Communications · doi:10.1038/ncomms11992 · Cited by 91 · see citing works
Restoring neuronal progranulin reverses deficits in a mouse model of frontotemporal dementia
Arrant, A. E., Filiano, A. J., Unger, D. E., Young, A. H., & Roberson, E. D. (2017) · Brain · doi:10.1093/brain/awx060 · Cited by 86 · see citing works
Pereson, S., Wils, H., Kleinberger, G., McGowan, E. M., Vandewoestyne, M., Broeck, B. V., Joris, G., Cuijt, I., Deforce, D. L. D., Hutton, M. L., et al. (2009) · The Journal of Pathology · doi:10.1002/path.2580 · Cited by 84 · see citing works
Initiative, A. D. N., Takahashi, H., Klein, Z. A., Bhagat, S. M., Kaufman, A. C., Kostylev, M. A., Ikezu, T., & Strittmatter, S. M. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1668-z · Cited by 83 · see citing works
Sasaki, A., Arawaka, S., Sato, H., & Kato, T. (2015) · Scientific Reports · doi:10.1038/srep14211 · Cited by 80 · see citing works
Progranulin Gene Delivery Protects Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease
Van Kampen, J. M., Baranowski, D., & Kay, D. G. (2014) · PLoS ONE · doi:10.1371/journal.pone.0097032 · Cited by 76 · see citing works
Beach, T. G., Sue, L. I., Walker, D. G., Sabbagh, M. N., Serrano, G., Dugger, B. N., Mariner, M., Yantos, K., Henry-Watson, J., Chiarolanza, G., et al. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-111340 · Cited by 74 · see citing works
Self-citationAlzheimer’s Disease: Advances in Drug Development
Piton, M., Hirtz, C., Desmetz, C., Milhau, J., Lajoix, A. D., Bennys, K., Lehmann, S., & Gabelle, A. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180145 · Cited by 60 · cited 1× · see citing works
“The interactions of PGRN and PSAP are complex as both PSAP reduction and overexpression resulted in elevated levels of extracellular/secreted PGRN in different cellular models [4].”
BackgroundRetinoic acid treatment of human neuroblastoma cells is associated with decreased N-myc expression
AMATRUDA, T. T., Sidell, N., Ranyard, J., & Koeffler, H. P. (1985) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(85)90311-0 · Cited by 59 · see citing works
Progranulin Reduction Is Associated With Increased Tau Phosphorylation in P301L Tau Transgenic Mice
Hosokawa, M., Arai, T., Masuda‐Suzukake, M., Kondo, H., Matsuwaki, T., Nishihara, M., Hasegawa, M., & Akiyama, H. (2015) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000158 · Cited by 58 · see citing works
TMEM106B expression is reduced in Alzheimer’s disease brains
Satoh, J., Kino, Y., Kawana, N., Yamamoto, Y., Ishida, T., Saito, Y., & Arima, K. (2014) · Alzheimer s Research & Therapy · doi:10.1186/alzrt247 · Cited by 51 · see citing works
Walker, D. G., Tang, T. M., & Lue, L. (2018) · Experimental Neurology · doi:10.1016/j.expneurol.2018.07.016 · Cited by 51 · see citing works
Self-citationGRN Variant rs5848 Reduces Plasma and Brain Levels of Granulin in Alzheimer's Disease Patients
Kämäläinen, A., Viswanathan, J., Natunen, T., Helisalmi, S., Kauppinen, T., Pikkarainen, M., Pursiheimo, J., Alafuzoff, I. I., Kivipelto, M., Haapasalo, A., et al. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-120946 · Cited by 50 · see citing works
PLD3 is accumulated on neuritic plaques in Alzheimer’s disease brains
Satoh, J., Kino, Y., Yamamoto, Y., Kawana, N., Ishida, T., Saito, Y., & Arima, K. (2014) · Alzheimer s Research & Therapy · doi:10.1186/s13195-014-0070-5 · Cited by 50 · see citing works
Progranulin Protein Levels in Cerebrospinal Fluid in Primary Neurodegenerative Dementias
Morenas‐Rodríguez, E., Cervera‐Carles, L., Vilaplana, E., Alcolea, D. A., Carmona‐Iragui, M., Dols‐Icardo, O., Nogué, R. R., Muñoz, L., Sala, I., Sánchez‐Saudinós, M. B., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150746 · Cited by 50 · see citing works
Andersson, A. K., Remnestål, J., Nellgård, B., Vunk, H., Kotol, D., Edfors, F., Uhlén, M., Schwenk, J. M., Ilag, L. L., Zetterberg, H., et al. (2019) · Clinica Chimica Acta · doi:10.1016/j.cca.2019.03.243 · Cited by 50 · see citing works
Kampen, J. M. V., & Kay, D. G. (2017) · PLoS ONE · doi:10.1371/journal.pone.0182896 · Cited by 47 · see citing works
Zhou, X., Sullivan, P. M., Sun, L., & Hu, F. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14110 · Cited by 44 · see citing works
Sortilin Fragments Deposit at Senile Plaques in Human Cerebrum
Hu, X., Hu, Z., Li, Z., Ruan, C., Qiu, W., Pan, A., Li, C.-Q., Cai, Y., Shen, L., Chu, Y., et al. (2017) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2017.00045 · Cited by 32 · see citing works
Arrant, A. E., Filiano, A. J., Patel, A. R., Hoffmann, M. Q., Boyle, N. R., Kashyap, S. N., Onyilo, V. C., Young, A. H., & Roberson, E. D. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.11.011 · Cited by 28 · see citing works
Zhou, F., Jiang, J., Griffith, C. M., Patrylo, P. R., Cai, H., Chu, Y., & Yan, X. (2018) · Alzheimer s Research & Therapy · doi:10.1186/s13195-018-0370-2 · Cited by 25 · see citing works
Mao, Q., Wang, D., Li, Y., Kohler, M., Wilson, J., Parton, Z., Shmaltsuyeva, B., Gursel, D. B., Rademakers, R., Weıntraub, S., et al. (2017) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlx085 · Cited by 24 · see citing works
Prosaposin Overexpression following Kainic Acid-Induced Neurotoxicity
Nabeka, H., Uematsu, K., Takechi, H., Shimokawa, T., Yamamiya, K., Li, C., Doihara, T., Saito, S., Kobayashi, N., & Matsuda, S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0110534 · Cited by 23 · see citing works
Gliebus, G. P., Rosso, A. L., & Lippa, C. F. (2009) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/1533317509346209 · Cited by 22 · see citing works
Optimizing Western Blots for the Detection of Endogenous α-Synuclein in the Enteric Nervous System
Preterre, C., Corbillé, A.-G., Balloy, G., Letournel, F., Neunlist, M., & Derkinderen, P. (2015) · Journal of Parkinson s Disease · doi:10.3233/jpd-150670 · Cited by 18 · see citing works
Nabeka, H., Saito, S., Li, X., Shimokawa, T., Khan, S., Yamamiya, K., Kawabe, S., Doihara, T., Hamada, F., Kobayashi, N., et al. (2017) · IBRO Reports · doi:10.1016/j.ibror.2017.07.001 · Cited by 18 · see citing works
Walker, D. G., Lue, L., Beach, T., & Tooyama, I. (2019) · Cells · doi:10.3390/cells8070766 · Cited by 15 · see citing works
Self-citationMa, Y., Matsuwaki, T., Yamanouchi, K., & Nishihara, M. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.05.003 · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Walker, D. G., Tang, T. M., Mendsaikhan, A., Tooyama, I., Serrano, G. E., Sue, L. I., Beach, T. G., & Lue, L.-F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21020678 · Cited by 128 · see citing works
Self-citationAndersen, J. V., Skotte, N. H., Christensen, S. K., Polli, F. S., Shabani, M., Markussen, K. H., Haukedal, H., Westi, E. W., Diaz-delCastillo, M., Sun, R. C., et al. (2021) · Cell Death & Disease · doi:10.1038/s41419-021-04237-y · Cited by 104 · see citing works
Sharoar, M. G., Palko, S., Ge, Y., Saido, T. C., & Yan, R. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00464-1 · Cited by 78 · see citing works
A critical appraisal of tau‐targeting therapies for primary and secondary tauopathies
Imbimbo, B. P., Ippati, S., Watling, M., & Balducci, C. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12453 · Cited by 72 · see citing works
Kluever, V., Russo, B., Mandad, S., Kumar, N. H., Alevra, M., Ori, A., Rizzoli, S. O., Urlaub, H., Schneider, A., & Fornasiero, E. F. (2022) · Science Advances · doi:10.1126/sciadv.abn4437 · Cited by 69 · see citing works
Secreted Chaperones in Neurodegeneration
Chaplot, K., Jarvela, T. S., & Lindberg, I. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00268 · Cited by 59 · see citing works
Gaucher disease: Basic and translational science needs for more complete therapy and management
Grabowski, G. A., Antommaria, A. H. M., Kolodny, E. H., & Mistry, P. K. (2020) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2020.12.291 · Cited by 59 · see citing works
Alzheimer’s Disease: Advances in Drug Development
Piton, M., Hirtz, C., Desmetz, C., Milhau, J., Lajoix, A. D., Bennys, K., Lehmann, S., & Gabelle, A. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180145 · Cited by 60 · see citing works
Progranulin in neurodegenerative dementia
Wang, X., Zeng, P. H., Fang, Y., Zhang, T., & Tian, Q. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15378 · Cited by 38 · see citing works
Takahashi, H., Bhagwagar, S. Z., Nies, S. H., Ye, H., Han, X., Chiasseu, M., Wang, G., Mackenzie, I. R., & Strittmatter, S. M. (2024) · Nature Communications · doi:10.1038/s41467-024-45692-3 · Cited by 32 · see citing works
Fairbrother-Browne, A., Ali, A. T., Reynolds, R. H., García-Ruiz, S., Zhang, D., Chen, Z., Ryten, M., & Hodgkinson, A. (2021) · Communications Biology · doi:10.1038/s42003-021-02792-w · Cited by 22 · see citing works
Zhou, X., Kukar, T. L., & Rademakers, R. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-51140-1_14 · Cited by 21 · see citing works
Luo, D., Li, J., Liu, H., Wang, J., Xia, Y., Qiu, W., Wang, N., Wang, X., Wang, X., Ma, C., et al. (2023) · Advanced Science · doi:10.1002/advs.202300876 · Cited by 21 · see citing works
Novel Therapies for Parkinsonian Syndromes–Recent Progress and Future Perspectives
Przewodowska, D., Marzec, W. Z., & Madetko‐Alster, N. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.720220 · Cited by 19 · see citing works
Microglia Biomarkers in Alzheimer’s Disease
Zhang, P., Hu, H., Tan, L., & Yu, J. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02348-3 · Cited by 18 · see citing works
Mendsaikhan, A., Tooyama, I., Serrano, G. E., Beach, T. G., & Walker, D. G. (2021) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlab056 · Cited by 17 · see citing works
Self-citationFang, S., Zhong, L., Wang, A.-Q., Zhang, H., & Yin, Z. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02289-x · Cited by 17 · see citing works
Microtubule-modulating Agents in the Fight Against Neurodegeneration: Will it ever Work?
Soliman, A., Bakota, L., & Brandt, R. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666211201101020 · Cited by 17 · see citing works
Hu, Z., Yang, J., Zhang, S., Li, M., Zuo, C., Mao, C., Zhang, Z., Tang, M., Shi, C., & Xu, Y. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-01277 · Cited by 15 · see citing works
Song, S.-S., Oft, H., Metwally, S. A. H., Paruchuri, S. S., Bielanin, J., Fiesler, V. M., Sneiderman, C. T., Kohanbash, G., & Sun, D. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03065-z · Cited by 13 · see citing works
Extracellular chaperone networks and the export of J-domain proteins
Braun, J. E. A. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102840 · Cited by 13 · see citing works
Prosaposin: A Multifaceted Protein Orchestrating Biological Processes and Diseases
Li, X., & Guo, L. (2025) · Cells · doi:10.3390/cells14151131 · Cited by 13 · see citing works
The role of endolysosomal progranulin and TMEM106B in neurodegenerative diseases
Takahashi, H., & Strittmatter, S. M. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00873-6 · Cited by 13 · see citing works
Blusztajn, J. K., Aytan, N., Rajendiran, T. M., Mellott, T. J., Soni, T., Burant, C., Serrano, G. E., Beach, T. G., Lin, H., & Stein, T. D. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230543 · Cited by 12 · see citing works
Self-citationChen, K. S., Noureldein, M. H., McGinley, L. M., Hayes, J. M., Rigan, D. M., Kwentus, J. F., Mason, S. N., Mendelson, F. E., Savelieff, M. G., & Feldman, E. L. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1306004 · Cited by 13 · see citing works
Microtubule-modulating Agents in the Fight Against Neurodegeneration: Will it ever Work?
Soliman, A., Bakota, L., & Brandt, R. (2022) · UCL Discovery (University College London) · Cited by 12 · see citing works
Loss of <i>Inpp5d</i> has disease‐relevant and sex‐specific effects on glial transcriptomes
Dabin, L. C., Kersey, H., Kim, B., Acri, D. J., Sharify, D., Lee‐Gosselin, A., Lasagna‐Reeves, C. A., Oblak, A. L., Lamb, B. T., & Kim, J. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13901 · Cited by 10 · see citing works
“47,48 These findings indicate that upregulation of PSAP expression in astrocytes and microglia may promote astrocyte reactivity and be neuroprotective.”
Yin, P., Wang, H., Xue, T., Yu, X., Meng, X., Mi, Q., Song, S., Xiong, B., Bi, Y., & Yu, L. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c00181 · Cited by 7 · see citing works
Bayaraa, O., Aksu, M., DeBose-Scarlett, E. M., Hocke, E., Jain, V. K., Wang, S. J., Cruz, D. A., & Gregory, S. G. (2025) · Human Genomics · doi:10.1186/s40246-025-00875-x · Cited by 8 · see citing works
Gharbi, T., Liu, C., Khan, H. L., Zhang, Z., Yang, G., & Tang, Y. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45030127 · Cited by 7 · see citing works
Ye, J., Wen, Z., Wu, T., Chen, L., Sheng, L., Wang, C., Teng, C., Wu, B., Xu, J., & Wei, W. (2023) · Advanced Biology · doi:10.1002/adbi.202300098 · Cited by 6 · see citing works
Adeoye, T., Shah, S. I., & Ullah, G. (2024) · Aging and Disease · doi:10.14336/ad.2024.0429 · Cited by 6 · see citing works
The MR1/MAIT cell axis enhances dystrophic neurite development in Alzheimer's disease
Wyatt‐Johnson, S. K., Ackley, S., Warren, J., Priya, R., Wan, J., Liu, S., & Brutkiewicz, R. R. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.14480 · Cited by 4 · see citing works
“19 Of note, the Mapt (microtubule-associated protein tau) gene that encodes tau, which is important in axonal stability, 20 was increased in its expression in 5XFAD/MR1 KO mice (Figure 3B).”
Prosaposin in CNS health and disease, metabolic stress and exercise adaptation
Taha, H. B., Zhu, S., & Wang, E. (2026) · Journal of Molecular Medicine · doi:10.1007/s00109-026-02643-3 · Cited by 5 · see citing works
Prosaposin Is Cleaved Into Saposins by Multiple Cathepsins in a Progranulin‐Regulated Fashion
Hodul, M., Lane‐Donovan, C., Cheang, E. S., Gao, V., Sampognaro, P. J., Mambou, E. A., Yang, Z., & Kao, A. W. (2026) · Journal of Neurochemistry · doi:10.1111/jnc.70357 · Cited by 3 · see citing works
Dan, X., Croteau, D. L., Liu, W., Chu, X., McDevitt, R. A., Robbins, P. D., & Bohr, V. A. (2026) · Nature Neuroscience · doi:10.1038/s41593-026-02390-1 · Cited by 3 · see citing works
Localization of Thioredoxin-Interacting Protein in Aging and Alzheimer’s Disease Brains
Tsubaki, H., Mendsaikhan, A., Buyandelger, U., Tooyama, I., & Walker, D. G. (2022) · NeuroSci · doi:10.3390/neurosci3020013 · Cited by 3 · see citing works
Self-citationThe Insight into the Role of Protein Misfolding and Tau Oligomers in Alzheimer’s Disease
Pandey, P., Kumar, C., & Khandia, R. (2025) · Springer eBooks · doi:10.1007/978-981-96-6202-9_12 · Cited by 3 · see citing works
Anstötz, M., Tschirner, S. K., May, C., Kösters, S., Martin, C., Caspers, S., Aronica, E., Bidmon, H. J., Marcus, K., & Korth, C. (2025) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.70043 · Cited by 2 · see citing works
Cerebrospinal Fluid Proteome Reveals Dysregulation of Lysosomal and Axonal Proteins in Neurosyphilis
Tang, H., Hu, J., Wu, Y., Gao, J., Wang, W., Zheng, X., Zhang, R., Liang, B., Zhou, F., & Guo, Z. (2026) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5c00689 · Cited by 2 · see citing works
Significant expression of prosaposin in the intermediate lobe of mouse pituitary gland
Fuyuki, A., Higuchi, M., Homma, T., Kitamura, K., Onouchi, S., & Saito, S. (2026) · Cell and Tissue Research · doi:10.1007/s00441-026-04054-9 · Cited by 2 · see citing works
Wang, X., Dai, L., Wu, N., Wu, D., Wang, X., Meng, X., Zhang, Q., Lu, J., Yan, X., Zhang, J., et al. (2025) · MedComm · doi:10.1002/mco2.70156 · Cited by 1 · see citing works
Takahashi, H., Bhagwagar, S. Z., Nies, S. H., Chiasseu, M., Wang, G., Mackenzie, I. R., & Strittmatter, S. M. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.12.25.521308 · Cited by 1 · see citing works
Klimmt, J., Gonçalves, C. C., Montgomery, J. V., Müller, S. A., Bublitz, M., Filser, S., Paeger, L., Nuscher, B., Dannert, A., Roeber, S., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.20.699077 · Cited by 1 · see citing works
Pgrn Alleviates Cerebral Amyloid-β Burden and Cognitive Impairments via Mediating NeuroinflammationPreprint
Xu, W., Tan, C., Cao, X., Yu, J., & Tan, L. (2020) · doi:10.21203/rs.3.rs-32425/v1
Fairbrother-Browne, A., Ali, A. T., Reynolds, R. H., García-Ruiz, S., Zhang, D., Chen, Z., Ryten, M., & Hodgkinson, A. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.02.04.429781
PGRN Alleviates Cerebral Amyloid-β Burden and Cognitive Impairments via Mediating NeuroinflammationPreprint
Xu, W. G., Tan, C., Cao, X., Yu, J., & Tan, L. (2020) · Research Square · doi:10.21203/rs.3.rs-51744/v1
The roles of prosaposin in neurological disorders: current understandings and prospects
Li, J., & Li, C. (2023) · Human Brain · doi:10.37819/hb.3.1781
Song, S., Oft, H., Metwally, S. A. H., Paruchuri, S. S., Bielanin, J. P., Fiesler, V. M., Sneiderman, C. T., Kohanbash, G., & Sun, D. (2024) · Figshare · doi:10.6084/m9.figshare.25449003
Sharoar, M. G., Palko, S. I., Ge, Y., Saido, T. C., & Yan, R. (2021) · Figshare · doi:10.6084/m9.figshare.14903777
Sharoar, M. G., Palko, S. I., Ge, Y., Saido, T. C., & Yan, R. (2021) · Figshare · doi:10.6084/m9.figshare.14903780
Hisaki, H., Susa, T., Okudaira, N., Akimoto, M., Iizuka, M., Matsuda, J., Uchida, S., Okinaga, H., Okazaki, T., & Tamamori-Adachi, M. (2025) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2025.102388
de Lavergne, M., Mazzola, L., Podsypanina, K., Estrella, C., Verwaerde, P., Evnouchidou, I., Darrasse-Jèze, G., Potier, M., Vyas, S., & Manoury, B. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.16.699962
Poniatowski, Ł. A., Siwińska, A., Acewicz, A., Kwiatkowska, M., & Olczak, M. (2026) · Forensic Science International · doi:10.1016/j.forsciint.2026.112829
遠山, 育., Mendsaikhan, A., Tooyama, I., SERRANO, G. E., Beach, T. G., & Walker, D. G. (n.d.) · Institutional Repositories DataBase (IRDB)
Self-citation遠山, 育., Walker, D. G., Tang, T. M., Mendsaikhan, A., Tooyama, I., SERRANO, G. E., Sue, L. I., BEARCH, T. G., & Lue, L. (2020) · Institutional Repositories DataBase (IRDB)
Self-citationCallizot, N., Culley, G. R., Flower, G., Rouvière, L., Conto, V. D., Wojcinski, A., Botto, C., Estrella, C., Henriques, A., & Verwaerde, P. (2026) · PLoS ONE · doi:10.1371/journal.pone.0359269
Ding, J., Samvelian, D. A., Ying, Z., Diamante, G., Ahn, I. S., Palafox-Sánchez, V., Wang, S. S.-M., Gómez‐Pinilla, F., & Yang, X. (2026) · iScience · doi:10.1016/j.isci.2026.117920
- Authors
- Mendsaikhan, A., Tooyama, I., Bellier, J.-P., Serrano, G. E., Sue, L. I., Lue, L.-F., Beach, T. G., & Walker, D. G.
- Affiliations
- Shiga University of Medical Science (JP)
- Banner Sun Health Research Institute (US)
- Corresponding author
- Walker, Douglas G.
- ORCID
- Venue
- Acta Neuropathologica Communications
- Published
- 2019-12
- Volume
- 7
- Issue
- 1
- Pages
- 215-215
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC6925443
- OpenAlex
- W2995562100
- Cited by
- 57
- References
- 74
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 7 · 2023: 6 · 2022: 5 · 2021: 14 · 2020: 6 · 2018: 1
- FWCI
- 4.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (JP17H03560)
- 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
- progranulin, prosaposin, Alzheimer's disease, amyloid plaques, lysosomal proteins, tau phosphorylation, LAMP1, protein-protein interaction, middle temporal gyrus, neurofibrillary tangles, sortilin, brain aging, frontotemporal dementia
- MeSH terms
- Progranulins, Aged, 80 and over, Alzheimer Disease, Cells, Cultured, Female, Humans, Lysosomes, Male, Neurons, Temporal Lobe, Microglia, Saposins, Plaque, Amyloid
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
