Scientists in South Korea have used intravenous injections of human adipose-derived stem cells (hADSCs) both to prevent development of and reverse the symptoms and neuropathology of Alzheimer’s disease (AD) in mouse models. The studies, in the Tg2576 mouse model of AD, demonstrated that either intravenous or intracerebral injections of hASCs led to significant improvements in memory and learning, and reduced the numbers of amyloid plaques and Aβ levels in the brain. The benefits were evident for at least four months after treatment.
Prior in vivo studies have demonstrated that transplanted neural stem cells and bone marrow-derived mesenchymal stem cells can help rescue memory deficits in AD mouse models and hold back Aβ deposition, but neither of these stem cell types would be suitable for intravenous administration, according to Seoul National University’s Yoo-Hun Suh, Ph.D., and the RNL Bio Stem Cell Technology Institute’s Jeong-Chan Ra, Ph.D. Another source of stem cells is the adipose tissue, which yields adipose-derived stem cells, a mesenchymal stem cell type that can differentiate into both mesenchymal and non-mesenchymal lineages. In contrast with other stem cell types, autologous hASCs are not associated with ethical issues, and, based on data from the team’s previous research, can be administered intravenously with no concerns about immune rejection or tumorigenesis.
In the first known study of its kind, the Seoul researchers have now shown not only that intravenously administered hASCs can traverse the blood-brain-barrier and engraft in the brain, but that either intravenous or intracerebral hASC therapy results in dramatic cognitive improvements in Alzheimer’s disease mice. These benefits were associated with reduced numbers of amyloid plaques and decreased levels of Aβ and amyloid precursor protein C-terminal fragment (APP-CT) through the induction of neprilysin, which hydrolyzes toxic proteins. Critically, when the hASCs were administered intravenously to young AD mice, the treatment completely prevented plaque formation.
Further analyses showed that intravenous and intracerebral administration of the stem cells was associated with increased brain levels of IL-10 and neurotrophic factors, including VEGF and GDNF, which directly suppressed neuronal cell death. In vitro studies indicated that the hASCs themselves produced IL-10, and stimulated additional IL-10 production by microglial cells. And when transplanted directly into the brain, the hASCs induced cell division and neurodifferentiation of endogenous neuroprogenitors in the hippocampus, and stabilized dendrites and synapses.
“We conclude that intracerebrally or intravenously injected hASCs dramatically improved learning and memory ability and decreased neuropathology of Tg2576 mice by diminishing the formation of amyloid plaques, decreasing Aβ and C-terminal levels and upregulating IL-10, VEGF, and elevating endogenous neurogenesis and synaptic and dendritic stability,” the authors researchers conclude. “Although it is yet unclear how hASCs upregulated IL-10 and growth factors such as VEGF and GDNF, our findings that intravenously transplanted hASCs prevent the onset and progression of the disease clearly provide an important preclinical platform for the development of prevention and therapy for AD patients.”