| First Author | Chen S | Year | 2025 |
| Journal | PLoS Biol | Volume | 23 |
| Issue | 6 | Pages | e3003259 |
| PubMed ID | 40587559 | Mgi Jnum | J:386955 |
| Mgi Id | MGI:8220689 | Doi | 10.1371/journal.pbio.3003259 |
| Citation | Chen S, et al. (2025) Gnb5 is a negative regulator of the BACE1-mediated Abeta generation and ameliorates cognitive deficits in a mouse model of Alzheimer's disease. PLoS Biol 23(6):e3003259 |
| abstractText | beta-Amyloid (Abeta) is generated from the amyloid precursor protein (APP) through sequential cleavage by beta-site APP-cleaving enzyme 1 (BACE1) and gamma-secretase, where BACE1 acting as the rate-limiting enzyme. Elevated BACE1 levels in the brains of Alzheimer's disease (AD) patients implicate that dysregulated BACE1 expression is crucial to AD pathogenesis. However, the underlying regulatory mechanisms remain unclear. Here, we identified that the G protein subunit beta5 gene (Gnb5), a component of the G protein-coupled receptor (GPCR) signaling pathway, is significantly downregulated in both human AD patients and AD mouse models. Conditional knockout of Gnb5 in excitatory neurons resulted in cognitive impairments, whereas adeno-associated virus (AAV)-mediated overexpression of Gnb5 in the hippocampus ameliorated cognitive deficits and reduced Abeta deposition in 5xFAD mice. Mechanistically, we demonstrated that Gnb5 interacts with BACE1, modulating its expression and potentially influencing Abeta generation. We further identify the first tryptophan-aspartate domain (WD domain) of Gnb5 and the Ser81 residue as crucial for this regulation. Expression of this WD domain alone is sufficient to reduce Abeta deposition in 5xFAD mice, whereas a point mutation at Ser81 (S81L) abolishes this effect. Overall, our findings establish Gnb5 as a negative regulator of the BACE1-APP processing axis and unveil mechanistic insights into its role in Abeta-mediated AD pathogenesis. |
