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bioRxiv · 10.1101/2025.06.04.657876

Neurotrophic Factor-α1/carboxypeptidase E regulates critical protein networks to rescue neurodegeneration, defective synaptogenesis and impaired autophagy in Alzheimer's Disease mice

Xiao, L.·Sharma, P.·Yang, X.·Abebe, D.·Loh, Y. P.
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Abstract

BackgroundThe global aging population is increasingly inflicted with Alzheimers disease (AD), but a cure is still unavailable. Neurotrophic Factor-1/carboxypeptidase E (NF-1/CPE) gene therapy has been shown to prevent and reverse memory loss and pathology AD mouse models However, the mechanisms of action of NF-1/CPE are not fully understood. We investigated if a non-enzymatic form of NF-1/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-1/CPE in AD mice. MethodsAAV-human NF-1/CPE and a non-enzymatic form, NF-1/CPE -E342Q were delivered into hippocampus of 3xTg-AD mice and effects on cognitive function, neurodegeneration, synaptogenesis and autophagy were investigated. A quantitative proteomic analysis of hippocampus of 3xTg-AD mice with and without AAV-NF-1/CPE treatment was carried out. ResultsHippocampal delivery of AAV-NF-1/CPE-E342Q prevented memory loss, neurodegeneration and increase in activated microglia in 3xTg-AD mice, indicating its action is independent of its enzymatic activity. Quantitative proteomic analysis of hippocampus of 3xTg-AD mice that underwent NF-1/CPE gene therapy revealed differential expression of >2000 proteins involving many metabolic pathways. Of these, two new proteins down-regulated by NF-1/CPE: Nexin4 (SNX4) and Trim28 which increase A{beta} production and tau levels, respectively were identified. Western blot analysis verified that they were reduced in AAV-NF-1/CPE treated 3xTg-AD mice compared to untreated mice. Our proteomic analysis indicated synaptic organization as top signaling pathway altered as a response to CPE expression. Synaptic markers PSD95 and Synapsin1 were decreased in 3xTg-AD mice and were restored with AAV-NF-1/CPE treatment. Proteomic analysis hypothesized involvement of autophagic signaling pathway. Indeed, multiple proteins known to be markers of autophagy were down-regulated in 3xTg-AD mice, accounting for impaired autophagy. Expression of these proteins were upregulated in 3xTg-AD mice with NF-1/CPE gene therapy, thereby reversing autophagic impairment. ConclusionsThis study uncovered vast actions of NF-1/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{beta} accumulation to reverse memory loss and AD pathology in 3xTg-AD mice. AAV-NF-1/CPE gene therapy uniquely targets many metabolic levels, offering a promising holistic approach for AD treatment. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/657876v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@10e468forg.highwire.dtl.DTLVardef@3a78adorg.highwire.dtl.DTLVardef@c8d62forg.highwire.dtl.DTLVardef@165d118_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Xiao, L., Sharma, P., Yang, X., Abebe, D., Loh, Y. P.. 2025-06-08. Neurotrophic Factor-α1/carboxypeptidase E regulates critical protein networks to rescue neurodegeneration, defective synaptogenesis and impaired autophagy in Alzheimer's Disease mice. https://doi.org/10.1101/2025.06.04.657876

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