Implicative role of epidermal growth factor receptor and its associated signaling partners in the pathogenesis of Alzheimer’s disease

• Published in: Ageing research reviews 2023-01, Vol.83, p.101791, Article 101791
• Main Authors: Jayaswamy, Pavan K., Vijaykrishnaraj, M., Patil, Prakash, Alexander, Lobo Manuel, Kellarai, Adithi, Shetty, Praveenkumar
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer’s disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; AnxA1; AnxA2; EGFR; ErbB Receptors - metabolism; Gal-3 and tPA; Humans; Neuroinflammation; Signal Transduction - physiology
• ISSN: 1568-1637; 1872-9649
• DOI: 10.1016/j.arr.2022.101791

Epidermal growth factor receptor (EGFR) plays a pivotal role in early brain development, although its expression pattern declines in accordance with the maturation of the active nervous system. However, recurrence of EGFR expression in brain cells takes place during neural functioning decline and brain atrophy in order to maintain the homeostatic neuronal pool. As a consequence, neurotoxic lesions such as amyloid beta fragment (Aβ1–42) formed during the alternative splicing of amyloid precursor protein in Alzheimer’s disease (AD) elevate the expression of EGFR. This inappropriate peptide deposition on EGFR results in the sustained phosphorylation of the downstream signaling axis, leading to extensive Aβ1–42 production and tau phosphorylation as subsequent pathogenesis. Recent reports convey that the pathophysiology of AD is correlated with EGFR and its associated membrane receptor complex molecules. One such family of molecules is the annexin superfamily, which has synergistic relationships with EGFR and is known for membrane-bound signaling that contributes to a variety of inflammatory responses. Besides, Galectin-3, tissue-type activated plasminogen activator, and many more, which lineate the secretion of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-18) result in severe neuronal loss. Altogether, we emphasized the perspectives of cellular senescence up-regulated by EGFR and its associated membrane receptor molecules in the pathogenesis of AD as a target for a therapeutical alternative to intervene in AD. •EGFR regulates the fate of neural stem cells and promotes postnatal neuronal migration.•ADAM10 cleaves APP and generates Aβ1-42 which acts as a ligand for EGFR.•Aβ1–42 - EGFR induced GSK-3β alters metabolic signaling such as AMPK, Cdk5, Wnt, etc.•EGFR-mediated signaling causes colocalization of AnxA2, Gal-3, and t-PA.•EGFR inhibitors reduce the formation of Aβ1–42-NFTs in Alzheimer's Disease.