Human iPSC-NSC-Derived Extracellular Vesicles Can Alleviate Alzheimer's Disease-Linked Impairments in Mitochondria, mTOR Signaling, Autophagy, and Hippocampal Neurogenesis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 42304162.
- Also identified by DOI 10.1111/acel.70590 and PMC identifier 13272109.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Intranasal (IN) administrations of extracellular vesicles (EVs) derived from human-induced pluripotent stem cell (hiPSC)-derived neural stem cells (hNSCs) have shown promise in reducing chronic neuroinflammation mediated by microglia and astrocytes in 5x familial Alzheimer's disease (5xFAD) mice, a model for early-onset Alzheimer's disease (AD). The current study rigorously investigated whether treatment with hiPSC-NSC-EVs could also alleviate several other neuropathological changes contributing to progressive cognitive decline. Three-month-old male and female 5xFAD mice received IN administrations of either hiPSC-NSC-EVs (~30 × 10<sup>9</sup>/week for 2 weeks) or vehicle. Two months later, the hippocampus of both male and female 5xFAD mice treated with the vehicle showed increased levels of markers of oxidative stress and mechanistic target of rapamycin (mTOR) signaling, altered expression of genes and/or proteins linked to mitochondria and autophagy, and diminished neurogenesis. In contrast, treatment with hiPSC-NSC-EVs restored levels of oxidative stress markers and the expression of genes and/or proteins linked to various mitochondrial complexes, mitochondrial biogenesis, fission, fusion, and mitophagy closer to naïve control levels, indicating alleviation of mitochondrial impairments. These improvements were accompanied by reduced phosphorylated mTOR levels and multiple autophagy markers matching those in naïve controls, suggesting a dampening of mTOR signaling and an enhancement of autophagy. Furthermore, mice treated with hiPSC-NSC-EVs showed increased hippocampal neurogenesis, associated with enhanced brain-derived neurotrophic factor signaling. Overall, the results highlight that IN administrations of hiPSC-NSC-EVs in the early stages of AD can help slow the progression of multiple neuropathological changes associated with cognitive decline in 5xFAD mice and potentially AD.
Medical subject headings
- Alzheimer Disease
- TOR Serine-Threonine Kinases
- Mitochondria
- Hippocampus
- Neurogenesis
- Induced Pluripotent Stem Cells
- Autophagy
- Extracellular Vesicles
- Neural Stem Cells