Microglia-targeted inhibition of miR-17 via mannose-coated lipid nanoparticles improves pathology and behavior in a mouse model of Alzheimer’s disease

• Published in: Brain, behavior, and immunity Vol. 119; pp. 919 - 944
• Main Authors: Badr, Asmaa, Daily, Kylene P., Eltobgy, Mostafa, Estfanous, Shady, Tan, Michelle H., Chun-Tien Kuo, Jimmy, Whitham, Owen, Carafice, Cierra, Gupta, Gauruv, Amer, Heba M., Shamseldin, Mohamed M., Yousif, Amir, Deems, Nicholas P., Fitzgerald, Julie, Yan, Pearlly, Webb, Amy, Zhang, Xiaoli, Pietrzak, Maciej, Ghoneim, Hazem E., Dubey, Purnima, Barrientos, Ruth M., Lee, Robert J., Kokiko-Cochran, Olga N., Amer, Amal O.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.07.2024
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Amyloid beta; Amyloid beta-Peptides - metabolism; Animals; Antagomirs - administration & dosage; Antagomirs - pharmacology; Brain - drug effects; Brain - metabolism; Disease Models, Animal; Lipid nanoparticles; Lipids; Male; Mannose - pharmacology; Mannose-coated nanoparticles; Mice; Mice behavior; Mice, Transgenic; Microglia; Microglia - drug effects; Microglia - metabolism; MicroRNA; MicroRNAs - metabolism; miR-17; Nanoparticles - administration & dosage; Neuroinflammation; RNA sequencing; RNA sequencing; miR-17; Amyloid beta; MicroRNA; Alzheimer’s disease; Mannose-coated nanoparticles; Neuroinflammation; Mice behavior; Lipid nanoparticles; Microglia
• ISSN: 0889-1591; 1090-2139; 1090-2139
• DOI: 10.1016/j.bbi.2024.05.006

Schematic illustration of the effects of inhibiting miR-17 in microglia of 5XFAD mouse brains in vivo. Anti-17 MLNPs injected through the cisterna magna in 5XFAD mice are attached to mannose receptors on the surface of microglia and internalized. This leads to a significant and specific downregulation of miR-17 in microglia. Notably, Amyloid-beta loads in the brain are significantly reduced. MiR-17 inhibition in turn, decreases immune cell activation and infiltration, dampens neuroinflammation and reduces microglial ASC expression. Subsequently, the expression of synaptic genes is improved in 5XFAD mouse brains. Importantly, the behavior and memory of 5XFAD mice are improved. [Display omitted] •Mannose lipid nanoparticles selectively deliver miR-17 inhibitor, antagomir, to the microglia of 5XFAD mice when injected via intracisternal magna.•Inhibition of miR-17 in microglia decreases microglia and immune cell activation in the brains of 5XFAD mice.•Inhibition of miR-17 in microglia dampens neuroinflammation and decreases amyloid beta deposition.•Microglial miR-17 inhibition in 5XFAD mice improved synaptic function and resulted in better anxiety and spatial memory behavioral tests performance. Neuroinflammation and accumulation of Amyloid Beta (Aβ) accompanied by deterioration of special memory are hallmarks of Alzheimer’s disease (AD). Effective preventative and treatment options for AD are still needed. Microglia in AD brains are characterized by elevated levels of microRNA-17 (miR-17), which is accompanied by defective autophagy, Aβ accumulation, and increased inflammatory cytokine production. However, the effect of targeting miR-17 on AD pathology and memory loss is not clear. To specifically inhibit miR-17 in microglia, we generated mannose-coated lipid nanoparticles (MLNPs) enclosing miR-17 antagomir (Anti-17 MLNPs), which are targeted to mannose receptors readily expressed on microglia. We used a 5XFAD mouse model (AD) that recapitulates many AD-related phenotypes observed in humans. Our results show that Anti-17 MLNPs, delivered to 5XFAD mice by intra-cisterna magna injection, specifically deliver Anti-17 to microglia. Anti-17 MLNPs downregulated miR-17 expression in microglia but not in neurons, astrocytes, and oligodendrocytes. Anti-17 MLNPs attenuated inflammation, improved autophagy, and reduced Aβ burdens in the brains. Additionally, Anti-17 MLNPs reduced the deterioration in spatial memory and decreased anxiety-like behavior in 5XFAD mice. Therefore, targeting miR-17 using MLNPs is a viable strategy to prevent several AD pathologies. This selective targeting strategy delivers specific agents to microglia without the adverse off-target effects on other cell types. Additionally, this approach can be used to deliver other molecules to microglia and other immune cells in other organs.