APH1a, also known as anterior pharynx-defective 1A, is an integral component of the γ-secretase complex. The γ-secretase complex is involved in multiple biological processes, most notably in the cleavage of the amyloid-precursor protein, which is a key event in the amyloid-β (Aβ) pathogenic cascade related to Alzheimer's disease (AD) [1,4].

Emerging evidence shows that G protein-coupled receptor kinases (GRKs) phosphorylate APH1a, generating distinct phosphorylation barcodes in its intracellular loop 2 (ICL2) and C-terminus. These barcodes differentially regulate the recruitment of the scaffolding protein β-arrestin 2 (βarr2) to APH1a and γ-secretase-mediated Aβ generation. Molecular dynamics simulation studies reveal an interaction between the βarr2 finger loop domain and ICL2 and ICL3 of APH1a, similar to a GPCR-β-arrestin complex, which regulates γ-secretase activity [1]. Also, miR-151-5p has been found to target APH1a, and blocking miR-151 can upregulate APH1a protein levels and impair hippocampal fear memory formation, indicating its role in memory-related processes [2]. Additionally, a Mendelian randomization analysis suggests that an existing small molecule inhibitor of the APH1A gene has the potential to increase FEV1, implicating its possible role in chronic obstructive pulmonary disease (COPD) [3].

In conclusion, APH1a is a crucial component of the γ-secretase complex, playing important roles in processes related to Alzheimer's disease, memory formation, and potentially in chronic obstructive pulmonary disease. The findings from studies on APH1a, including those related to its phosphorylation by GRKs, regulation by miR-151-5p, and potential as a drug target in COPD, contribute to a better understanding of these disease mechanisms and may offer new therapeutic strategies.