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Neuregulin 1/ErbB4/Akt signaling attenuates cytotoxicity mediated by the APP-CT31 fragment of amyloid precursor protein
- Source :
- Experimental and molecular pathology. 120
- Publication Year :
- 2020
-
Abstract
- Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by neuronal and synaptic loss. The cytoplasmic tail of amyloid precursor protein (APP) undergoes sequential cleavage at a specific intracellular caspase site to generate the cytoplasmic terminal 31 (CT31) fragment. The APP-CT31 fragment is a potent inducer of apoptosis. The cytotoxicity of APP-CT31 in SH-SY5Y cells was evaluated by the lactate dehydrogenase (LDH) assay. TUNEL staining was used to detect apoptotic signals in SH-SY5Y cells and primary cortical neurons. The expression of apoptosis-related proteins, such as p53, PUMA (p53 up-regulated modulator of apoptosis), and cleaved was investigated by immunofluorescence analysis and Western blotting. In this study, we investigated the neuroprotective effect of neuregulin 1 (NRG1) against cytotoxicity induced by APP-CT31. Our data showed that CT31 induced cytotoxicity and apoptosis in SH-SY5Y cells and primary cortical neurons. NRG1 attenuated the neurotoxicity induced by the expression of APP-CT31. We also showed that APP-CT31 altered the expression of p53 and cleaved caspase 3. However, treatment with NRG1 rescued the APP-CT31-induced upregulation of p53 and cleaved caspase 3 expression. The protective effect of NRG1 was abrogated by inhibition of the ErbB4 receptor and Akt. These results indicate an important role of ErbB4/Akt signaling in NRG1-mediated neuroprotection, suggesting that endogenous NRG1/ErbB4 signaling represents a valuable therapeutic target in AD.
- Subjects :
- 0301 basic medicine
Receptor, ErbB-4
Neuregulin-1
Clinical Biochemistry
Caspase 3
Apoptosis
Neuroprotection
Pathology and Forensic Medicine
03 medical and health sciences
Amyloid beta-Protein Precursor
Neuroblastoma
0302 clinical medicine
Protein Domains
mental disorders
Amyloid precursor protein
medicine
Tumor Cells, Cultured
Humans
Neuregulin 1
Cytotoxicity
Molecular Biology
Protein kinase B
Caspase
Cell Proliferation
biology
Chemistry
Neurotoxicity
medicine.disease
Cell biology
030104 developmental biology
Neuroprotective Agents
030220 oncology & carcinogenesis
biology.protein
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 10960945
- Volume :
- 120
- Database :
- OpenAIRE
- Journal :
- Experimental and molecular pathology
- Accession number :
- edsair.doi.dedup.....276e63f96788a85c477d788fa94a712f