Improvement of Cognitive Impairment Induced by Hearing Loss

Background

Alzheimer’s Disease (AD) is a common dementia characterized by extracellular amyloid plaques formed by aggregation of amyloid-β (Aβ) and intracellular neurofibrillary tangles formed by aggregated tau protein. Epidemiological studies indicate a close correlation between hearing loss and the incidence of dementia, with significantly increased risk. However, the molecular mechanisms by which hearing loss promotes the onset of AD are not yet clear. Therefore, this study aims to explore the relationship between hearing loss and cognitive impairment and to investigate potential therapeutic targets.

Source of Research

The paper titled “GDF1 Ameliorates Cognitive Impairment Induced by Hearing Loss” was published in Nature Aging in April 2024. The study was collaboratively completed by the Departments of Neurology from Renmin Hospital and Zhongnan Hospital of Wuhan University, the Department of Otolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, the Molecular Imaging Center of Wuhan University, and the Taikang Center for Life Sciences at Wuhan University. The corresponding author is Dr. Zhentao Zhang from Renmin Hospital of Wuhan University.

Research Summary

Research Process

Research Steps and Experimental Methods:

1. Model Establishment and Confirmation: Hearing loss models were established in 3-month-old wild-type (WT) mice and APP/PS1 transgenic mice through bilateral cochlear ablation (CA) and kanamycin injection. One month post-surgery, hearing loss was confirmed through auditory brainstem response (ABR).
2. Cognitive and Pathological Assessments: Aβ deposition in the hippocampus, auditory cortex, and temporal lobe cortex was detected by immunohistochemistry and Thioflavin S staining at different time points post-surgery. Learning and memory abilities were evaluated using Morris water maze and Y maze tests.
3. Synaptic Function Assessment: Changes in synaptic density in the hippocampus were observed through electron microscopy, and synaptic protein expression levels were analyzed by immunoblotting.
4. RNA Sequencing and Gene Function Research: RNA sequencing analysis was conducted 6 months post-surgery to explore the potential molecular mechanisms underlying cognitive impairment induced by hearing loss.

Experimental Results:

1. Hearing Loss Triggers AD-like Pathology and Cognitive Impairment: Hearing loss promotes cognitive impairment through increased Aβ deposition and synaptic dysfunction. Six months post-surgery, CA mice showed significantly longer latencies in the Morris water maze test and reduced time spent in the target zone during the probe test.
2. Decreased GDF1 Expression and Its Impact on Cognitive Function: RNA sequencing revealed that growth/differentiation factor 1 (GDF1) was significantly downregulated in the hippocampus of hearing loss mice. Knockdown of GDF1 replicated the harmful cognitive effects of hearing loss, while overexpression of GDF1 alleviated hearing loss-induced cognitive impairment. Immunoblotting showed that GDF1 activates the AKT signaling pathway, interfering with the activity of asparagine endopeptidase (AEP) through phosphorylation, thereby inhibiting AEP-induced synaptic degeneration and Aβ generation.
3. Molecular Mechanism Analysis: GDF1 regulates AEP activity through the AKT signaling pathway, reducing AD-like synaptic pathology. Further analysis showed that the transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) inhibited GDF1 expression, suggesting that C/EBPβ plays an important role in the link between hearing loss and cognitive impairment.

Research Conclusions

Hearing loss promotes AD-like pathological changes and cognitive impairment by inhibiting the GDF1 signaling pathway, identifying GDF1 as a potential therapeutic target for AD. This study reveals the crucial role of GDF1 in cognitive impairment induced by hearing loss and provides a new perspective for the molecular mechanism research of AD.

Research Highlights

1. Revealed the Molecular Mechanism Between Hearing Loss and AD: The study first discovered the key role of GDF1 in hearing loss-induced AD pathology.
2. Expanded New Targets for AD Research: Identified GDF1 as a potential target for the treatment of AD and other dementias.
3. Validation through Various Experimental Techniques: Systematically analyzed the molecular mechanisms of hearing loss by integrating multiple experimental techniques such as RNA sequencing, immunohistochemistry, and behavioral tests.

Conclusions and Prospects

This study provides an in-depth understanding of the molecular mechanisms between hearing loss and AD, marking a new chapter for GDF1 as a potential target for the treatment of AD. Future studies should further explore the role of GDF1 in other cognitive dysfunctions and develop therapeutic strategies based on the GDF1 signaling pathway. This will bring new hope for the prevention and treatment of AD.