Abstract
Cognitive aging is a leading public health concern with the increasing aging population, but there is still lack of specific interventions directed against it. Recent studies have shown that cognitive function is intimately affected by systemic milieu in aging brain, and improvement of systemic environment in aging brain may be a promising approach for rejuvenating cognitive aging. Here, we sought to study the intervention effects of clinical-grade human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on cognitive aging in a murine model of aging. The conventional aging model in mice induced by d-galactose (d-gal) was employed here. Mice received once every two weeks intraperitoneal administration of hUC-MSCs. After 3 months of systematical regulation of hUC-MSCs, the hippocampal-dependent learning and memory ability was effectively improved in aged mice, and the synaptic plasticity was remarkably enhanced in CA1 area of the aged hippocampus; moreover, the neurobiological substrates that could impact on the function of hippocampal circuits were recovered in the aged hippocampus reflecting in: dendritic spine density enhanced, neural sheath and cytoskeleton restored, and postsynaptic density area increased. In addition, the activation of the endogenic neurogenesis which is beneficial to stabilize the neural network in hippocampus was observed after hUC-MSCs transplantation. Furthermore, we demonstrated that beneficial effects of systematical regulation of hUC-MSCs could be mediated by activation of mitogen-activated protein kinase (MAPK)-ERK-CREB signaling pathway in the aged hippocampus. Our study provides the first evidence that hUC-MSCs, which have the capacity of systematically regulating the aging brain, may be a potential intervention for cognitive aging.
Highlights
Cognitive aging is a lifelong process of ongoing and gradual cognitive function decline in the senior
We expanded the primary cells to Passage 5 (P5) and Passage 15 (P15), which were sent to the National Institutes for Food and Drug Control (NIFDC) for comprehensive quality test
We examined CA1 pyramidal cells in the middle third of the stratum radiatum (Figure 3c) and granule cells in dentate gyrus (DG) (Figure 3c) by electron microscopy and the results showed that postsynaptic density (PSD) area decreased in the asymmetrical synapses of D-gal-PBS mice
Summary
Cognitive aging is a lifelong process of ongoing and gradual cognitive function decline in the senior. It has gradually been recognized that the aging systemic milieu negatively regulates cognitive function in aging brain, reflecting in impaired spatial learning and memory, decreased synaptic plasticity and neurogenesis and so on. We hypothesized that hUC-MSCs, as young stem cells,[11] may be a superior source for reversing cognitive aging by providing circulating multifunctional factors and improve systemic environment. We selected a D-galactose (D-gal)-induced aging model, a systemic and homogeneous aging model with the acceleration of aging and cognitive deficits.[12,13,14] To observe the systematic regulation effects in aging brain by the secreted multifunctional factors from hUC-MSCs, hUC-MSCs were infused into the D-galinduced aging mice intraperitoneally.
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