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Targeted ErbB4 receptor activation prevents D-galactose-induced neuronal senescence via inhibiting ferroptosis
Ji-Ji Dao1,2, Wei Zhang1,3, Chong Liu1,2
1Cell Biology Department, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
Background:
Neuronal senescence is a common pathological feature of various neurodegenerative diseases, with ferroptosis playing a significant role. This study aims to investigate the role of ErbB4 receptor activation in preventing D-Galactose (D-gal)-induced neuronal senescence.
Methods:
Mice subjected to D-gal-induced aging were administered a small molecule ErbB4 receptor agonist (E4A), identified via virtual screening, melatonin, or a combination of both. Behavioral assessments were conducted to evaluate therapeutic efficacy in memory and cognitive functions. Immunofluorescence staining, western blot, and biochemical assays were primarily employed to assess changes in both senescence- and ferroptosis-related molecules in mouse hippocampal tissues in response to each treatment. Additionally, mouse hippocampal HT22 neuronal cell cultures were utilized to corroborate the in vivo findings.
Results:
The targeted activation of ErbB4 receptor by E4A significantly ameliorated the behavioral deficits induced by D-gal in mice, demonstrating an effect comparable to that of melatonin, a natural inhibitor of in vivo senescence and ferroptosis. Both E4A and melatonin mitigated D-gal-induced aging in hippocampal neurons of mice. This was evidenced by the upregulation of Lamin B1 and the downregulation of P53, P21, P16, GFAP, and Iba-1 expression levels. Moreover, D-gal treatment markedly decreased the protein expression of the ferroptosis inhibitor Nrf2 while augmenting the expression of the ferroptosis promoter TFRC. These alterations were partially reversed by the individual administration of E4A and melatonin. In vitro studies further corroborated that D-gal treatment significantly and concurrently induced the expression of senescence markers and ferroptosis promoters. However, both E4A and melatonin were able to significantly reverse these changes. Additionally, E4A markedly ameliorated Erastin-induced ferroptosis in mouse hippocampal neuronal cells.
Conlusion:
Our findings suggest that targeted activation of ErbB4 receptor may be a viable strategy for treating neuronal senescence by inhibiting ferroptosis, thereby offering a potential therapeutic avenue for senescence-associated neurodegenerative diseases.
Insights
Targeted ErbB4 receptor activation with E4A effectively combats D-galactose-induced neuronal senescence and ferroptosis in mice. This approach shows promise for treating neurodegenerative diseases linked to aging.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Neuronal senescence is a hallmark of neurodegenerative diseases, with ferroptosis significantly contributing to pathology.
- D-galactose (D-gal) is used to induce aging models in mice, mimicking aspects of neurodegeneration.
Purpose of the Study:
- To investigate the role of ErbB4 receptor activation in preventing D-galactose-induced neuronal senescence.
- To explore the therapeutic potential of a small molecule ErbB4 receptor agonist (E4A) and melatonin in mitigating neurodegeneration.
Main Methods:
- Mice received D-gal, E4A, melatonin, or a combination; behavioral, immunofluorescence, western blot, and biochemical assays were performed.
- HT22 neuronal cell cultures were used for in vitro validation of in vivo findings.
- Evaluated senescence markers (Lamin B1, P53, P21, P16) and ferroptosis markers (Nrf2, TFRC, Erastin).
Main Results:
- E4A treatment significantly improved cognitive and memory deficits in D-gal-induced aging mice, comparable to melatonin.
- Both E4A and melatonin reversed D-gal-induced changes in senescence and ferroptosis markers in mouse hippocampus.
- In vitro studies confirmed E4A and melatonin reversed D-gal-induced senescence and ferroptosis, with E4A ameliorating Erastin-induced ferroptosis.
Conclusions:
- Targeted ErbB4 receptor activation by E4A is a potential therapeutic strategy for neuronal senescence.
- Inhibiting ferroptosis via ErbB4 activation offers a novel avenue for treating senescence-associated neurodegenerative diseases.
