Integrative analysis of microRNA-mediated mitochondrial dysfunction in hippocampal neural progenitor cell death in relation with Alzheimer's disease

Adult hippocampal neurogenesis plays a pivotal role in maintaining cognitive brain function; however, this process diminishes with age, particularly in patients with neurodegenerative disorders. While small, non-coding microRNAs (miRNAs) are crucial for hippocampal neural stem (HCN) cell maintenance, their involvement in neurodegenerative disorders remains unclear. This study aims to elucidate the mechanisms through which miRNAs regulate HCN cell death and their potential involvement in neurodegenerative disorder. We performed a comprehensive microarray-based analysis to investigate changes in miRNA expression in insulin-deprived HCN cells, as an in vitro model for cognitive impairment. Remarkably, miR-150-3p, miR-323-5p, and miR-370-3p which increased significantly over time following insulin withdrawal, induced pronounced mitochondrial fission and dysfunction, ultimately leading to HCN cell death. Notably, these miRNAs collectively target the mitochondrial fusion protein OPA1, with miR-150-3p also targeting MFN2. Furthermore, data-driven analyses involving human subjects within the hippocampus and brain revealed significant reductions of OPA1 and MFN2 in the Alzheimer's disease (AD) patients. Our results indicate that miR-150-3p, miR-323-5p, and miR-370-3p contribute to deficits in hippocampal neurogenesis by modulating mitochondrial dynamics. Our findings provide a novel insight into the intricate connection between miRNAs and mitochondrial dynamics, shedding light on their potential involvement in conditions characterized by deficits in hippocampal neurogenesis, such as AD.

Relationship Between Neutralizing Antibodies Against Adeno-Associated Virus in the Vitreous and Serum: Effects on Retinal Gene Therapy.

PURPOSE: We determine the prevalence of neutralizing antibodies (NAbs) to adeno-associated virus (AAV) in the vitreous humor and serum of patients with vitreoretinal diseases and investigate the relationship between NAb titers in the vitreous humor and serum. METHODS: We analyzed NAbs to AAV serotypes 2, 5, 8, and 9 via in vitro neutralization in the vitreous humor and serum from 32 patients requiring vitrectomy for vitreoretinal diseases. The blood-retinal barrier (BRB) was evaluated for integrity based on preoperative examinations, with vitreous hemorrhage (VH) on funduscopy or dye leakage on fluorescein angiography observed indicating disruption. RESULTS: NAb levels were much lower in the vitreous humor than in the serum regardless of serotype. Patients with VH had higher levels of NAbs in the vitreous humor than those without VH. The NAb ratio (ratio between NAb titers in the serum and vitreous humor) was much lower in patients with epiretinal membrane with than in those without leakage. A significantly lower NAb ratio was noticed in patients with than in those without BRB disruptions. CONCLUSIONS: The NAb ratio between levels in serum and vitreous humor varies according to the condition of the BRB. Therefore, in addition to measuring the serum NAb level, physicians should examine BRB integrity when planning retinal gene therapy. TRANSLATIONAL RELEVANCE: This study provides substantial basis for retinal gene therapy using AAVs and how maintenance of BRB integrity in target diseases should be considered.