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

Lan Xiao, Pranav Sharma, Xuyu Yang, Daniel Abebe, Y Peng Loh

Erratum issuedAbstract read

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Article in Translational neurodegeneration, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 1 paper.

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1citing papers in PubMed

–field-weighted citation impact

1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

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3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

Correction: Neurotrophic factor-α1/carboxypeptidase E regulates critical protein networks to rescue neurodegeneration, defective synaptogenesis and impaired autophagy in Alzheimer's disease mice.Translational neurodegeneration · 2026
Article

4 · The record

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5 · Who and what money

Authors and funding

5 authors.

Lan XiaoSection on Cellular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 49, Convent Drive, Bldg. 49, Rm 6A-10, NICHD, NIH, Bethesda, MD, 20892, USA.

Pranav SharmaXosomix LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA. sharma@xosomix.com.ORCID http://orcid.org/0000-0003-4064-4049

Xuyu YangSection on Cellular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 49, Convent Drive, Bldg. 49, Rm 6A-10, NICHD, NIH, Bethesda, MD, 20892, USA.

Daniel AbebeSection on Cellular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 49, Convent Drive, Bldg. 49, Rm 6A-10, NICHD, NIH, Bethesda, MD, 20892, USA.

Y Peng LohSection on Cellular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 49, Convent Drive, Bldg. 49, Rm 6A-10, NICHD, NIH, Bethesda, MD, 20892, USA. lohp@mail.nih.gov.ORCID http://orcid.org/0000-0002-5404-723X

Funding

National Institute of Child Health and Human Development Intramural research grant

6 · The paper itself

Abstract

backgroundThe global aging population is increasingly inflicted with Alzheimer's disease (AD), but a cure is still unavailable. Neurotrophic factor-α1/carboxypeptidase E (NF-α1/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-α1/CPE are not fully understood. We investigated if a non-enzymatic form of NF-α1/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-α1/CPE in AD mice.

methodsAAV-human NF-α1/CPE or a non-enzymatic form, NF-α1/CPE-E342Q, was delivered into the hippocampus of 3 × Tg-AD male mice. The effects on cognitive function, neurodegeneration, synaptogenesis and autophagy were investigated. A quantitative proteomic analysis of the hippocampus was carried out.

resultsHippocampal delivery of AAV-NF-α1/CPE-E342Q prevented memory loss, neurodegeneration and microglial activation in 3 × Tg-AD mice, indicating that the action is independent of its enzymatic activity. Quantitative proteomic analysis of the hippocampus of 3 × Tg-AD mice revealed differential expression of > 2000 proteins involving many metabolic pathways after NF-α1/CPE gene therapy. Of these, two new proteins, Snx4 and Trim28, which increase Aβ production and tau levels, respectively, were down-regulated by NF-α1/CPE. Western blot analysis verified their reduction in AAV-NF-α1/CPE-treated 3 × Tg-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 × Tg-AD mice and were restored with AAV-NF-α1/CPE treatment. Proteomic analysis hypothesized involvement of autophagic signaling pathway. Indeed, multiple protein markers of autophagy were down-regulated in 3 × Tg-AD mice, accounting for impaired autophagy. NF-α1/CPE gene therapy upregulated the levels of these proteins in 3 × Tg-AD mice, thereby reversing autophagic impairment.

conclusionsThis study uncovered vast actions of NF-α1/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 Aβ accumulation to reverse memory loss and AD pathology in 3 × Tg-AD mice. AAV-NF-α1/CPE gene therapy uniquely targets many metabolic levels, offering a promising holistic approach for AD treatment (Graphical Abstract).

Indexed as

Alzheimer DiseaseAutophagyCarboxypeptidase HSynapsesAnimalsDisease Models, AnimalGenetic TherapyHippocampusHumansMaleMiceMice, Inbred C57BLMice, TransgenicProteomicsCarboxypeptidase H3 × Tg ADAlzheimer’s diseaseAutophagyGene therapyNeurodegenerationNeurotrophic Factor-α1/carboxypeptidase E (NF-α1/CPE)Synaptogenesis

Identifiers

PMID41291954

DOI10.1186/s40035-025-00520-6

PMCPMC12648813

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.