Nano‐Brake Halts Mitochondrial Dysfunction Cascade to Alleviate Neuropathology and Rescue Alzheimer's Cognitive Deficits. Issue 7 (26th January 2023)

• Record Type: Journal Article
• Authors: Zhang, Qian; Song, Qingxiang; Yu, Renhe; Wang, Antian; Jiang, Gan; Huang, Yukun; Chen, Jun; Xu, Jianrong; Wang, Dayuan; Chen, Hongzhuan; Gao, Xiaoling
• Is Part Of: Advanced science. Volume 10:Issue 7(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-26
• Subjects: Alzheimer's disease -- Ca2+ homeostasis -- mitochondrial dysfunction -- mitochondrial permeability transition pore -- nanotherapeutics; Science -- Periodicals; 505
• DOI: 10.1002/advs.202204596
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: Mitochondrial dysfunction has been recognized as the key pathogenesis of most neurodegenerative diseases including Alzheimer's disease (AD). The dysregulation of mitochondrial calcium ion (Ca 2+ ) homeostasis and the mitochondrial permeability transition pore (mPTP), is a critical upstream signaling pathway that contributes to the mitochondrial dysfunction cascade in AD pathogenesis. Herein, a "two‐hit braking" therapeutic strategy to synergistically halt mitochondrial Ca 2+ overload and mPTP opening to put the mitochondrial dysfunction cascade on a brake is proposed. To achieve this goal, magnesium ion (Mg 2+ ), a natural Ca 2+ antagonist, and siRNA to the central mPTP regulator cyclophilin D (CypD), are co‐encapsulated into the designed nano‐brake; A matrix metalloproteinase 9 (MMP9) activatable cell‐penetrating peptide (MAP) is anchored on the surface of nano‐brake to overcome the blood‐brain barrier (BBB) and realize targeted delivery to the mitochondrial dysfunction cells of the brain. Nano‐brake treatment efficiently halts the mitochondrial dysfunction cascade in the cerebrovascular endothelial cells, neurons, and microglia and powerfully alleviates AD neuropathology and rescues cognitive deficits. These findings collectively demonstrate the potential of advanced design of nanotherapeutics to halt the key upstream signaling pathways of mitochondrial dysfunction to provide a powerful strategy for AD modifying therapy. Abstract : Matrix metalloproteinase 9 activatable cell‐penetrating peptide (MAP) on the nano‐brake mediates its efficient entry into the target cells. With siRNA reducing the expression of cyclophilin D and magnesium ion suppressing calcium ion overload, nano‐brake halts the overall mitochondrial dysfunction cascade in the cerebrovascular endothelial cells, neurons, astrocytes and microglia and largely alleviates the neuropathology and cognitive deficits of Alzheimer's disease.