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Neurotrophic factor-\u03b11\/carboxypeptidase E (NF-\u03b11\/CPE) gene therapy has been shown to prevent and reverse memory loss and pathology in AD mouse models. However, the mechanisms of action of NF-\u03b11\/CPE are not fully understood. We investigated if a non-enzymatic form of NF-\u03b11\/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-\u03b11\/CPE in AD mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>AAV-human NF-\u03b11\/CPE or a non-enzymatic form, NF-\u03b11\/CPE-E342Q, was delivered into the hippocampus of 3\u2009\u00d7\u2009Tg-AD male mice. The effects on cognitive function, neurodegeneration, synaptogenesis and autophagy were investigated. A quantitative proteomic analysis of the hippocampus was carried out.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Hippocampal delivery of AAV-NF-\u03b11\/CPE-E342Q prevented memory loss, neurodegeneration and microglial activation in 3\u2009\u00d7\u2009Tg-AD mice, indicating that the action is independent of its enzymatic activity. Quantitative proteomic analysis of the hippocampus of 3\u2009\u00d7\u2009Tg-AD mice revealed differential expression of\u2009&gt;\u20092000 proteins involving many metabolic pathways after NF-\u03b11\/CPE gene therapy. Of these, two new proteins, Snx4 and Trim28, which increase A\u03b2 production and tau levels, respectively, were down-regulated by NF-\u03b11\/CPE. Western blot analysis verified their reduction in AAV-NF-\u03b11\/CPE-treated 3\u2009\u00d7\u2009Tg-AD mice compared to untreated mice. Our proteomic analysis indicated synaptic organization as the top signaling pathway altered in response to CPE expression. Synaptic markers PSD95 and Synapsin1 were decreased in 3\u2009\u00d7\u2009Tg-AD mice and were restored with AAV-NF-\u03b11\/CPE treatment. Proteomic analysis hypothesized involvement of autophagic signaling pathway. Indeed, multiple protein markers of autophagy were down-regulated in 3\u2009\u00d7\u2009Tg-AD mice, accounting for impaired autophagy. NF-\u03b11\/CPE gene therapy upregulated the levels of these proteins in 3\u2009\u00d7\u2009Tg-AD mice, thereby reversing autophagic impairment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study uncovered vast actions of NF-\u03b11\/CPE in restoring expression of networks of critical proteins including those necessary for maintaining neuronal survival, synaptogenesis and autophagy, while down-regulating many proteins that promote tau and A\u03b2 accumulation to reverse memory loss and AD pathology in 3\u2009\u00d7\u2009Tg-AD mice. AAV-NF-\u03b11\/CPE gene therapy uniquely targets many metabolic levels, offering a promising holistic approach for AD treatment (Graphical Abstract).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40035-025-00520-6","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T02:27:35Z","timestamp":1764124055000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Neurotrophic factor-\u03b11\/carboxypeptidase E regulates critical protein networks to rescue neurodegeneration, defective synaptogenesis and impaired autophagy in Alzheimer\u2019s disease mice"],"prefix":"10.1186","volume":"14","author":[{"given":"Lan","family":"Xiao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4064-4049","authenticated-orcid":false,"given":"Pranav","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuyu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Abebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5404-723X","authenticated-orcid":false,"given":"Y. 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