This study effectively ameliorates cognitive dysfunction, synaptic formation defects, and autophagy dysfunction in an Alzheimer's disease mouse model through gene therapy using NF-α1/CPE and its non-enzymatic form E342Q. Proteomic analysis reveals that NF-α1/CPE regulates multiple key signaling pathways, including those related to synaptic organization and autophagy, offering new mechanistic insights into Alzheimer’s disease treatment.
Literature Overview
This article, 'Neurotrophic factor-α1/carboxypeptidase E regulates critical protein networks to rescue neurodegeneration, defective synaptogenesis and impaired autophagy in Alzheimer’s disease mice', published in the journal Translational Neurodegeneration, reviews and summarizes the neuroprotective effects of NF-α1/CPE gene therapy in the 3 × Tg-AD mouse model. The study further explores the regulatory mechanisms of multiple key signaling pathways modulated by NF-α1/CPE, such as synaptic organization and autophagy-related proteins, offering systemic mechanistic clues for Alzheimer’s disease treatment.
Background Knowledge
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder primarily characterized by β-amyloid (Aβ) deposition, hyperphosphorylation of tau protein, synaptic loss, and autophagy dysfunction. Although several mouse models (e.g., 3 × Tg-AD, 5 × FAD) simulate AD pathology, the molecular mechanisms remain incompletely understood. NF-α1/CPE is a multifunctional neuroprotective factor whose non-enzymatic form, E342Q, has shown neuroprotective effects in prior studies. This study further explores its regulatory effects on AD-associated protein networks by delivering NF-α1/CPE or the non-enzymatic variant NF-α1/CPE-E342Q via AAV injection into the mouse hippocampus. The research aims to determine whether NF-α1/CPE improves AD pathology through a non-enzymatic mechanism and systematically analyzes the regulated protein networks to identify novel therapeutic targets.
Research Methods and Experiments
The study employed the 3 × Tg-AD mouse model and delivered NF-α1/CPE or its non-enzymatic variant NF-α1/CPE-E342Q via adeno-associated virus (AAV) injection into the hippocampus. Subsequently, behavioral tests (Morris water maze and open field test) were conducted to assess recovery of cognitive function. Proteomic analysis (LC-MS/MS) was used to profile protein expression changes in the hippocampus, with particular validation of synaptic formation-related proteins (e.g., PSD95, Synapsin1) and autophagy-related proteins (Beclin1, LC3, ATG7). Additionally, Western blot, immunohistochemistry, and electron microscopy were performed to validate the regulatory effects of NF-α1/CPE on Aβ and tau pathology.
Key Conclusions and Perspectives
Research Significance and Prospects
This study reveals that NF-α1/CPE improves neurodegenerative lesions, synaptic formation impairments, and autophagy defects in AD mouse models by regulating multiple key protein networks. This provides a systemic regulatory strategy for AD therapy and supports NF-α1/CPE as a potential therapeutic agent. Future studies should assess its efficacy in non-human primate models and explore whether its regulatory mechanisms apply to human neurons, thus advancing clinical translation.
Conclusion
This study successfully ameliorated cognitive deficits, neurodegeneration, and autophagy dysfunction in 3 × Tg-AD mice through AAV-mediated delivery of NF-α1/CPE and its E342Q mutant. Proteomic analysis identified multiple key signaling pathways regulated by NF-α1/CPE, including those involved in synaptic formation, autophagy regulation, and metabolic pathways, with Snx4 and Trim28 identified as novel AD-associated proteins. These findings deepen our understanding of the mechanisms underlying NF-α1/CPE-mediated neuroprotection in AD and provide a theoretical basis for developing protein network-targeted gene therapies. This research opens new directions for AD treatment and suggests that NF-α1/CPE may serve as a key component in multi-target therapeutic strategies.
