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Systemic Treatment with siRNA Targeting Gamma-Secretase Activating Protein Inhibits Amyloid-ß Accumulation in Alzheimer's Disease.
Kim, Sunghwa; Ullah, Irfan; Beloor, Jagadish; Chung, Kunho; Kim, Jongkil; Yi, Yujong; Kang, Eunhwa; Yun, Gyeongju; Heo, Seoyoun; Pyun, Seon-Hong; Kim, Seung Hyun; Kumar, Priti; Lee, Sang-Kyung.
Afiliación
  • Kim S; Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea.
  • Ullah I; Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea.
  • Beloor J; Department of Internal Medicine, Yale University, New Haven, CT, USA.
  • Chung K; Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea.
  • Kim J; Department of Internal Medicine, Yale University, New Haven, CT, USA.
  • Yi Y; Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea.
  • Kang E; Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Yun G; Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea.
  • Heo S; Harvard Medical School, Boston, MA, USA.
  • Pyun SH; Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea.
  • Kim SH; Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea.
  • Kumar P; Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea.
  • Lee SK; Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea.
Biomater Res ; 28: 0027, 2024.
Article en En | MEDLINE | ID: mdl-38868092
ABSTRACT
Amyloid-ß (Aß) peptide aggregation in the brain is a key factor in Alzheimer's disease. However, direct inhibition of ß-secretase or γ-secretase proves ineffective in reducing Aß accumulation and improving cognition in Alzheimer's. Recent findings suggest that inhibiting gamma-secretase activating protein (GSAP) can decrease Aß generation without affecting crucial γ-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, diLep9R3LCsiRNA 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, diLep9R3LCsiGSAP 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 diLep9R3LCsiGSAP 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 Aß accumulation, reduces GSK-3ß-associated with tau hyperphosphorylation, and improves Alzheimer's behavior. Our findings highlight diLep9R3LCsiGSAP's potential for Alzheimer's and as a siRNA carrier for central nervous system-related diseases.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Biomater Res Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Biomater Res Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos