| First Author | Kim S | Year | 2024 |
| Journal | Biomater Res | Volume | 28 |
| Pages | 0027 | PubMed ID | 38868092 |
| Mgi Jnum | J:359552 | Mgi Id | MGI:7787219 |
| Doi | 10.34133/bmr.0027 | Citation | Kim S, et al. (2024) Systemic Treatment with siRNA Targeting Gamma-Secretase Activating Protein Inhibits Amyloid-beta Accumulation in Alzheimer's Disease. Biomater Res 28:0027 |
| abstractText | Amyloid-beta (Abeta) peptide aggregation in the brain is a key factor in Alzheimer's disease. However, direct inhibition of beta-secretase or gamma-secretase proves ineffective in reducing Abeta accumulation and improving cognition in Alzheimer's. Recent findings suggest that inhibiting gamma-secretase activating protein (GSAP) can decrease Abeta generation without affecting crucial gamma-secretase substrates. Dimerization of Lep9R3LC (diLep9R3LC) was confirmed by Ellman's test. The peptide-small interfering RNA (siRNA) complex ratio, particle size, and surface charge were analyzed using electrophoretic mobility shift assay, and dynamic light scattering, respectively. In a 3xTg mice model of Alzheimer's disease, diLep9R3LC:siRNA complexes were intravenously administered twice a week for 8 weeks. Assessments included gene silencing, protein expression, and behavioral improvement using reverse transcription polymerase chain reaction, quantitative polymerase chain reaction, western blotting, Y-maze, and object recognition tests. The efficacy of Lep9R3LC dimerization was ~80% after a 3-d reaction by Ellman's test. In N2a cells, diLep9R3LC:siGSAP complexes achieved ~70% silencing at 48 h posttransfection. In 7-month-old male 3xTg mice, GSAP knockdown was ~30% in the cortex and ~50% in the hippocampus. The behavior improved in mice treated with diLep9R3LC:siGSAP complexes, showing a 60% increase in entries and an 80% increase object recognition. A novel dipeptide, diLep9R3LC, complexed with siRNA targeting GSAP (siGSAP), efficiently delivers siRNA to the mouse brain, targeting the hippocampus. The treatment inhibits Abeta accumulation, reduces GSK-3beta-associated with tau hyperphosphorylation, and improves Alzheimer's behavior. Our findings highlight diLep9R3LC:siGSAP's potential for Alzheimer's and as a siRNA carrier for central nervous system-related diseases. |
