APH1a, short for anterior pharynx-defective 1A, is an integral component of the γ-secretase complex. γ-secretase is an intramembrane-cleaving protease involved in processing various protein substrates, including the amyloid precursor protein (APP) and Notch receptors, thus playing a crucial role in the amyloid-β (Aβ) pathogenic cascade in Alzheimer's disease (AD) and Notch signaling pathway, which is essential for cell-fate determination, proliferation, and differentiation [1,6,7].

GPCR kinases phosphorylate APH1A, generating distinct phosphorylation barcodes in intracellular loop 2 (ICL2) and the C-terminus. These barcodes differentially regulate the recruitment of the scaffolding protein β-arrestin 2 (βarr2) to APH1A and γ-secretase-mediated Aβ generation [1]. miR-151-5p modulates APH1a expression, and its elevation is responsible for hippocampal contextual fear memory formation. Blocking miR-151 can upregulate APH1a protein levels and impair hippocampal fear memory formation [2]. An existing small molecule inhibitor of the APH1A gene has the potential to increase FEV1, indicating its possible role in chronic obstructive pulmonary disease (COPD) [3]. Gingerol, a dietary compound, improves cognitive and behavioral impairment in streptozotocin-induced sporadic Alzheimer's disease model mice, with a decrease in APH1a activity [4]. In cell lines, the catabolism of overexpressed myc-tagged-APH1a was enhanced by proteasome inhibitors, while endogenous APH1a was not affected by these inhibitors under physiological conditions [5].

In conclusion, APH1a is crucial in the γ-secretase complex, with its phosphorylation, expression regulation, and activity influencing processes related to memory formation, AD, and potentially COPD. Studies on APH1a, including those using various experimental models, help to understand its role in these biological processes and disease conditions, potentially paving the way for novel therapeutic strategies.

References:

1. Todd, Nicholas K, Huang, Yunhong, Lee, Ji Young, Bahar, Ivet, Thathiah, Amantha. . GPCR kinases generate an APH1A phosphorylation barcode to regulate amyloid-β generation. In Cell reports, 40, 111110. doi:10.1016/j.celrep.2022.111110. https://pubmed.ncbi.nlm.nih.gov/35858570/

2. Xu, Xu-Feng, Wang, You-Cui, Zong, Liang, Wang, Xiao-Long. 2019. miR-151-5p modulates APH1a expression to participate in contextual fear memory formation. In RNA biology, 16, 282-294. doi:10.1080/15476286.2019.1572435. https://pubmed.ncbi.nlm.nih.gov/30663934/

3. Wang, Zihui, Li, Shaoqiang, Cai, Guannan, Hu, Jieying, Zheng, Jinping. 2024. Mendelian randomization analysis identifies druggable genes and drugs repurposing for chronic obstructive pulmonary disease. In Frontiers in cellular and infection microbiology, 14, 1386506. doi:10.3389/fcimb.2024.1386506. https://pubmed.ncbi.nlm.nih.gov/38660492/

4. Halawany, Ali M El, Sayed, Nesrine S El, Abdallah, Hossam M, Dine, Riham Salah El. 2017. Protective effects of gingerol on streptozotocin-induced sporadic Alzheimer's disease: emphasis on inhibition of β-amyloid, COX-2, alpha-, beta - secretases and APH1a. In Scientific reports, 7, 2902. doi:10.1038/s41598-017-02961-0. https://pubmed.ncbi.nlm.nih.gov/28588301/

5. Dunys, Julie, Kawarai, Toshitaka, Wilk, Sherwin, Alves da Costa, Cristine, Checler, Frédéric. . Catabolism of endogenous and overexpressed APH1a and PEN2: evidence for artifactual involvement of the proteasome in the degradation of overexpressed proteins. In The Biochemical journal, 394, 501-9. doi:. https://pubmed.ncbi.nlm.nih.gov/16302845/

6. Zhao, Guojun, Liu, Zhenyi, Ilagan, Ma Xenia G, Kopan, Raphael. . Gamma-secretase composed of PS1/Pen2/Aph1a can cleave notch and amyloid precursor protein in the absence of nicastrin. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 30, 1648-56. doi:10.1523/JNEUROSCI.3826-09.2010. https://pubmed.ncbi.nlm.nih.gov/20130175/

7. St George-Hyslop, P, Fraser, P E. 2011. Assembly of the presenilin γ-/ε-secretase complex. In Journal of neurochemistry, 120 Suppl 1, 84-88. doi:10.1111/j.1471-4159.2011.07505.x. https://pubmed.ncbi.nlm.nih.gov/22122073/