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NGF deficiency in the basal forebrain precedes degeneration of basal forebrain cholinergic neurons in Alzheimer's disease, contributing to memory decline. NGF mediates neurotrophic support via its high\u2010affinity receptor, the tropomyosin\u2010related kinase A (TrkA) receptor, and mediates mitogenic and differentiation signals via the extracellular signal\u2010regulated protein kinases 1 and 2 (ERK1\/2). However, the molecular mechanisms underlying the different NGF\/TrkA\/ERK signalling pathways are far from clear. In this study, we have investigated the role of human NGF and three NGF mutants, R100E, W99A and K95A\/Q96A, their ability to activate TrkA or ERK1\/2, and their ability to induce proliferation or differentiation in human foetal dorsal root ganglion (DRG) neurons or in PC12 cells. We show that the R100E mutant was significantly more potent than NGF itself to induce proliferation and differentiation, and significantly more potent in activation of ERK1\/2 in DRG neurons. The W99A and K95A\/Q96A mutants, on the other hand, were less effective than the wild\u2010type protein. An unexpected finding was the high efficacy of the K95A\/Q96A mutant to activate TrkA and to induce differentiation of DRG neurons at elevated concentrations. These data demonstrate an NGF mutant with improved neurotrophic properties in primary human neuronal cells. The R100E mutant represents an interesting candidate for further drug development in Alzheimer's disease and other neurodegenerative disorders.<\/jats:p>","DOI":"10.1111\/ejn.14513","type":"journal-article","created":{"date-parts":[[2019,7,13]],"date-time":"2019-07-13T19:59:49Z","timestamp":1563047989000},"page":"3487-3501","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Identification of amino acid residues of nerve growth factor important for neurite outgrowth in human dorsal root ganglion neurons"],"prefix":"10.1111","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9413-7846","authenticated-orcid":false,"given":"M\u00e4rta","family":"Dahlstr\u00f6m","sequence":"first","affiliation":[{"name":"Division of Clinical Geriatrics Department of Neurobiology, Care Sciences and Society Karolinska Institutet Huddinge Sweden"},{"name":"AlzeCure Foundation Huddinge Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gunnar","family":"Nordvall","sequence":"additional","affiliation":[{"name":"AlzeCure Foundation Huddinge Sweden"},{"name":"Division of Neurogeriatrics Department of Neurobiology, Care Sciences and Society Karolinska Institutet Huddinge Sweden"},{"name":"AlzeCure Pharma AB Huddinge Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik","family":"Sundstr\u00f6m","sequence":"additional","affiliation":[{"name":"Division of Neurogeriatrics Department of Neurobiology, Care Sciences and Society Karolinska Institutet Huddinge Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabet","family":"\u00c5kesson","sequence":"additional","affiliation":[{"name":"Division of Neurogeriatrics Department of Neurobiology, Care Sciences and Society Karolinska Institutet Huddinge Sweden"},{"name":"R&amp;D Unit Stockholms Sjukhem Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gunilla","family":"Tegerstedt","sequence":"additional","affiliation":[{"name":"Division of Gynecology and Obstetrics Department of Clinical Science, Intervention and Technology Karolinska Institutet Huddinge Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Eriksdotter","sequence":"additional","affiliation":[{"name":"Division of Clinical Geriatrics Department of Neurobiology, Care Sciences and Society Karolinska Institutet Huddinge Sweden"},{"name":"Theme Aging Karolinska University Hospital Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pontus","family":"Forsell","sequence":"additional","affiliation":[{"name":"AlzeCure Foundation Huddinge Sweden"},{"name":"Division of Neurogeriatrics Department of Neurobiology, Care Sciences and Society Karolinska Institutet Huddinge Sweden"},{"name":"AlzeCure Pharma AB Huddinge Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/157015911798376190"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ca.980080612"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1982.tb01207.x"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017321"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-012-8310-9"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.11.146"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh096"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1159\/000336051"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.14.5454"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-016-0195-9"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-141068"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/1087057113479401"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-015-0198-z"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560050306"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(91)90180-8"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1095190"},{"key":"e_1_2_10_18_1","volume-title":"The organization of behavior","author":"Hebb D. 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