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Irfan UllahIrfan Ullah

한양대학교

Biomater. Res., 2024, 28 | https://doi.org/10.34133/bmr.0027 Systemic Treatment with siRNA Targeting Gamma-Secretase Activating Protein Inhibits Amyloid-β Accumulation in Alzheimer's Disease

Sunghwa Kim ^1†, Irfan Ullah ^1,2†, Jagadish Beloor^1,2, Kunho Chung^1,3, Jongkil Kim^1,4, Yujong Yi ¹, Eunhwa Kang¹, Gyeongju Yun¹, Seoyoun Heo¹, Seon-Hong Pyun¹, Seung Hyun Kim ⁵, Priti Kumar ², Sang-Kyung Lee¹

¹Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea.

²Department of Internal Medicine, Yale University, New Haven, CT, USA.

³Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

⁴Harvard Medical School, Boston, MA, USA.

⁵Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea.

^†These authors contributed equally to this work.

^*Address correspondence to: Sang-Kyung Lee

Abstract

Amyloid-β (Aβ) peptide aggregation in the brain is a key factor in Alzheimer's disease. However, direct inhibition of β-secretase or γ-secretase proves ineffective in reducing Aβ accumulation and improving cognition in Alzheimer's. Recent findings suggest that inhibiting gamma-secretase activating protein (GSAP) can decrease Aβ 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, 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 Aβ accumulation, reduces GSK-3β-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.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-17)
연구진국내(교신)+국외 연구진
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