COGNITIVE FUNCTION-IMPROVING AND NEUROPROTECTIVE EFFECTS OF AN EXOSOME-RICH CONDITIONED MEDIUM FROM AMNIOTIC MEMBRANE STEM CELLS IN ALZHEIMER'S DISEASE MODEL ANIMALS

초록

Background and Aims: In Alzheimer's disease (AD), amyloid β (Aβ) peptide-mediated cholinergic degeneration causes depletion of acetylcholine (ACh), leading to cognitive dysfunction. Since current AD treatments using acetylcholinesterase inhibitors and Aβ antibodies do not reverse disease progression and cause adverse effects, more effective and safe treatments are required. Methods: An exosome-rich conditioned medium (ERCM) containing high concentrations of neprilysin (NEP) and growth and neurotrophic factors (GFs/NFs) was collected via hypoxic culture (2% O2) of human amniotic membrane stem cells (AMSCs). Penetration and cytoprotective activities of exosomes were assessed in normal, H2O2- or AF64Achallemged human neural stem cells (NSCs). The AD-therapeutic effects of ERCM were confirmed in AF64A-induced memory deficit mice. Results: CM-DiI-labeled exosomes entered normal and H2O2-damaged NSCs, and ERCM showed NEP activity and protected against AF64Ainduced NSC degeneration. Intracerebroventricular injection of AF64A induced cognitive dysfunction in passive avoidance and Morris watermaze performances. However, intravenous injection of ERCM (1.2 x 109 - 1.2 x 1010 particles/mouse) 4 times markedly recovered the learning and memory function. ERCM also preserved hippocampal pyramidal cells, decreased brain Aβ level, and restored ACh concentration. Neuroprotective and anti-inflammatory effects of ERCM were also confirmed by the recovery of GFs/NFs and cholinergic nerve markers and the decrease in glial fibrillary acidic protein-expressing astrocytes. In addition, nestin-positive host NSCs and choline acetyltransferase-expressing cholinergic neurons increased following treatment with ERCM. Conclusions: AMSC-ERCM containing large amounts of functional molecules such as NEP and GFs/NFs can ameliorate cognitive deficit of AD animals via Aβ elimination as well as neuroprotection and neuroregeneration.