The accumulation of extracellular β-amyloid (Aβ) plaques within the brain is unique to Alzheimer’s disease (AD) and thought to induce synaptic deficits and neuronal loss. Optimal therapies should tackle the core AD pathophysiology and prevent the decline in memory and cognitive functions. This study aimed to evaluate the therapeutic performance of mesenchymal stem cell-derived exosomes (MSC-exosomes), which are secreted membranous elements encapsulating a variety of MSC factors, on AD. A human neural cell culture model with familial AD (FAD) mutations was established and co-cultured with purified MSC-exosomes. 2-[¹⁸F]Fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) and novel object recognition (NOR) testing were performed before/after treatment to evaluate the therapeutic effect in vivo. The AD-related pathology and the expression of neuronal memory/synaptic plasticity-related genes were also evaluated. The results showed that MSC-exosomes reduced Aβ expression and restored the expression of neuronal memory/synaptic plasticity-related genes in the cell model. [¹⁸F]FDG-PET imaging and cognitive assessment revealed a significant improvement in brain glucose metabolism and cognitive function in AD transgenic mice. The phase of neurons and astrocytes in the brain of AD mice were also found to be regulated after treatment with MSC-exosomes. Our study demonstrates the therapeutic mechanism of MSC-exosomes and provides an alternative therapeutic strategy based on cell-free MSC-exosomes for the treatment of AD.

BACKGROUND: The purpose of the current study was to investigate a hospital series of 986 cases of primary pediatric brain tumors in Taiwan.METHODS: The authors reviewed the database of primary pediatric brain tumors in patients < 18 years of age collected in Taipei Veterans General Hospital (Taipei VGH) from 1975 to May 2004. Age and gender distribution, location, and classification of brain tumors were analyzed. Intracranial tumors with diagnostic imaging were included. Nontumoral lesions, cysts, and vascular malformations were excluded.RESULTS: The mean age of these 986 patients was 7.8 years, and the male to female ratio was 1.4:1. Supratentorial (including pineal–quadrigeminal) located tumors (58.3%) was predominant to infratentorial tumors (41.1%). In these series, 886 patients had either histologic diagnosis (842 patients) or clinical diagnosis (44 patients). The most common 5 categories of tumors were astrocytic tumors (31.1%), germ cell tumors (14.0%), medulloblastomas (13.3%), craniopharyngiomas (8.3%), and ependymal tumors (5.8%). Atypical teratoid/rhabdoid tumors (AT/RTs), a rare but highly malignant tumor, were 2.1%. The high incidence of primary intracranial germ cell tumors correlated with reported series from Japan and Korea. For the remaining 100 patients without diagnostic classifications, the majority were most likely astrocytic tumors in brain stem.CONCLUSIONS: The authors analyzed a large hospital series of primary brain tumors in children. Both histologically verified and unverified tumors were recruited to avoid selective bias. Although it was not a study of a population‐based brain tumor registry, it could still be representative of primary pediatric brain tumors in Taiwan. Cancer 2005. © 2005 American Cancer Society.

Atypical teratoid/rhabdoid tumor (AT/RT) is an extremely malignant neoplasm in the central nervous system (CNS) which occurs in infancy and childhood. Recent studies suggested that CD133 could be considered a marker for brain cancer stem-like cells (CSCs). However, the role of CD133 in AT/RT has never been investigated. Herein we report the isolation of CD133-positive cells (CD133⁺), found to have the potential to differentiate into three germ layer tissues, from tissues of nine AT/RT patients. The migration/invasion/malignancy and radioresistant capabilities of CD133⁺ were significantly augmented when compared to CD133⁻. The clinical data showed that the amount of CD133⁺ in AT/RTs correlated positively with the degree of resistance to radiation therapy. Using cDNA microarray analysis, the genotoxic–response profiles of CD133⁺ and CD133⁻ irradiated with 10 Gy ionizing radiation (IR) were analyzed 0.5, 2, 6, 12 and 24 h post-IR. We then validated these microarray data and showed increased phosphorylation after IR of p-ATM, p-RAD17, and p-CHX2 as well as increased expression of BCL-2 protein in CD133⁺ compared to CD133⁻. Furthermore, we found that CD133⁺ can effectively resist IR with cisplatin- and/or TRAIL-induced apoptosis. Immunohistochemical analysis confirmed the up-regulated expression of p-ATM and BCL-2 proteins in IR-treated CD133⁺ xenotransgrafts in SCID mice but not in IR-treated CD133⁻. Importantly, the effect of IR in CD133⁺ transplanted mice can be significantly improved by a combination of BCL-2 siRNA with debromohymenialdisine, an inhibitor of checkpoint kinases. In sum, this is the first report indicating that CD133⁺ AT/RT cells demonstrate the characteristics of CSCs. The IR-resistant and anti-apoptotic properties in CD133⁺ may reflect the clinical refractory malignancy of AT/RTs and thus the activated p-ATM pathway and BCL-2 expression in CD133⁺ could be possible targets to improve future treatment of deadly diseases like AT/RT.