ERBB4 and Neurodegeneration: Association Between Hypothalamic-Pituitary-Adrenal (HPA) Axis: Associated...

The hypothalamic-pituitary-adrenal (HPA) axis is the central neuroendocrine system that controls physiological stress responses and maintains homeostasis through the coordinated interactions among the hypothalamus, pituitary gland, and adrenal cortex. Dysregulation of the HPA axis is associated with stress-related psychiatric conditions and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Chronic stress creates a detrimental environment in the brain, inducing structural changes and accelerating brain aging and the loss of neurons. Receptor tyrosine-protein kinase ERBB4 (ERBB4), a member of the epidermal growth factor receptor (EGFR) family, is activated primarily by neuregulin ligands and plays an essential role in neuronal development, synaptic plasticity, and cell survival. Emerging evidence suggests that ERBB4 signaling influences neuroendocrine regulation and stress responsivity. While further studies are needed to provide direct mechanistic evidence linking ERBB4-mediated HPA axis dysregulation to neurodegenerative cell death, this manuscript critically evaluated the preclinical models and proposes a possible feed-forward framework wherein ERBB4 served as a permissive homeostatic modulator at the intersection of stress endocrinology and neuroinflammation. Furthermore, the impact of ERBB4 dysregulation and its mutations on neurodegenerative diseases has been presented, focusing on potential mechanisms of oxidative stress, synaptic dysfunction, and neuronal apoptosis. Taken together, ERBB4 represents an important molecular interface between stress signaling and neurodegenerative pathology. Understanding the regulation of ERBB4 in the HPA axis has provided new insights into the mechanisms underlying neurodegenerative diseases and could identify novel therapeutic targets for stress-associated neurological disorders.