Author: Yang Sun

Publisher: Guangdong-Hong Kong-Macao Central Nervous Regeneration Research Institute  

Date: October 22, 2024

On October 18, 2024, the Yang Su/Li Xiaojiang team from the Guangdong Hong Kong Macao Institute of Central Nervous Regeneration at Jinan University published a significant research paper titled Increased expression of mesenchymal stem-derived neurotrophic factor (MANF) contributes to synapse loss in Alzheimer's disease in the prestigious journal Molecular Neurogenesis.

Study Overview

Background:  

Endoplasmic reticulum (ER) stress has been identified as an early pathological feature in Alzheimer's disease (AD), yet its role in the disease's onset and progression remains underexplored. The study focuses on mesencephalic astrocyte-derived neurotrophic factor (MANF), an ER stress-inducible protein and non-canonical neurotrophic factor, whose increased levels have been observed in the brains of AD patients at both pre-symptomatic and symptomatic stages.

Methods:  

The researchers analyzed MANF expression in various stages of AD mouse models. They performed behavioral, electrophysiological, and neuropathological assessments to evaluate synaptic dysfunctions in MANF transgenic mice (which overexpress MANF) and wild type (WT) mice with MANF overexpression in the hippocampus. Additionally, they utilized proteomic and transcriptomic screenings to investigate the underlying molecular mechanisms of MANF's impact on synaptic functions.

 Key Findings

- The study revealed a correlation between elevated MANF levels and synapse loss in the hippocampus of AD mice.

- Ectopic expression of MANF (through transgenic or viral methods) induced synaptic loss and impairments in learning and memory.

- The research identified that MANF interacts with ELAV-like RNA-binding protein 2 (ELAVL2), influencing its association with RNA transcripts related to synaptic functions.

- Modifying MANF expression levels in the hippocampus of AD mice affected behavioral deficits and synaptic pathology: increasing MANF exacerbated issues, while decreasing it provided amelioration.

 Conclusion

This study positions MANF as a critical mechanistic link between ER stress and synapse loss in Alzheimer's disease, offering a promising therapeutic target for treating AD.

 Contributions and Support

Zhang Yiran, Chen Xiusheng, and Chen Laiqiang, all doctoral students at Jinan University, are co-first authors of the paper. Researcher Yang Su serves as the corresponding author, with Professors Li Xiaojiang and Li Shihua providing essential guidance and support. The research received funding from the National Key R&D Program (2021YFA0805200), the National Natural Science Foundation of China (319709548200113), and the Guangdong Provincial Department of Science and Technology Project (2021ZT09Y00720B121201006).

For further reading, the full article can be accessed [here] 

(https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-024-00771-3).