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The secreted extracellular domain of the amyloid precursor protein (sAPP\u03b1) has been shown to modulate neurite outgrowth. Recently, the gamma amino butyric acid receptor type-B subunit 1a (GABA\n                  <jats:sub>B<\/jats:sub>\n                  R1a) was identified as an sAPP\u03b1 binding partner that mediates its effects on synaptic transmission. Here, we investigated whether this interaction also regulates neurite outgrowth. In primary hippocampal neurons, the GABA\n                  <jats:sub>B<\/jats:sub>\n                  R agonist baclofen reduced axon length; whereas, its antagonist CGP54626 increased axon length in primary hippocampal neurons. Moreover, GABA\n                  <jats:sub>B<\/jats:sub>\n                  R1a knockout increased axon length and abolished the effect of baclofen. Application of sAPP\u03b1 reduced axon length, an effect that required the presence of both GABA\n                  <jats:sub>B<\/jats:sub>\n                  R1a and the extension domain of sAPP\u03b1, which mediates its binding to GABA\n                  <jats:sub>B<\/jats:sub>\n                  R1a. Similarly, the APP 17mer peptide, which is sufficient to bind GABA\n                  <jats:sub>B<\/jats:sub>\n                  R1a and mimic the effects of sAPP on synaptic transmission, reduced axon outgrowth in wildtype but not in GABA\n                  <jats:sub>B<\/jats:sub>\n                  R1a-deficient neurons. Together, these findings indicate that the 1a isoform contributes to GABA\n                  <jats:sub>B<\/jats:sub>\n                  R-dependent suppression of neurite outgrowth and mediates the inhibitory effect of sAPP\u03b1 on neurite outgrowth.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of Significance<\/jats:title>\n                  <jats:p>Amyloid precursor protein (APP) plays a central role in Alzheimer\u2019s disease, yet its normal functions are not fully understood. In this study, we uncover a previously unrecognized role of the GABA B Receptor in mediating the inhibitory effects of sAPP\u03b1 on neurite outgrowth. These findings provide mechanistic insight into how disruptions in APP signaling could influence both normal brain development and pathological processes in neurodevelopmental disorders and Alzheimer\u2019s disease.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.14.675870","type":"posted-content","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T08:40:16Z","timestamp":1757925616000},"source":"Crossref","is-referenced-by-count":1,"title":["sAPP\u03b1 inhibits neurite outgrowth in primary mouse neurons via GABA B Receptor subunit 1a"],"prefix":"10.64898","author":[{"given":"Dylan","family":"Barber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casandra","family":"Salinas-Salinas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samah","family":"Houmam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kriti","family":"Shukla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5818-4338","authenticated-orcid":false,"given":"Heather C.","family":"Rice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025091714201244000_2025.09.14.675870v1.1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00626.2006"},{"key":"2025091714201244000_2025.09.14.675870v1.2","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12051."},{"key":"2025091714201244000_2025.09.14.675870v1.3","doi-asserted-by":"crossref","unstructured":"Bony, G. , Szczurkowska, J. , Tamagno, I. , Shelly, M. , Contestabile, A. , & Cancedda, L. 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