Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment
- 3 June 2019
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 116 (25), 12524-12533
- https://doi.org/10.1073/pnas.1902672116
Abstract
Aging drives a progressive decline in cognition and decreases synapse numbers and synaptic function in the brain, thereby increasing the risk for neurodegenerative disease. Pioneering studies showed that introduction of blood from young mice into aged mice reversed age-associated cognitive impairments and increased synaptic connectivity in brain, suggesting that young blood contains specific factors that remediate age-associated decreases in brain function. However, whether such factors in blood from young animals act directly on neurons to enhance synaptic connectivity, or whether they act by an indirect mechanism remains unknown. Moreover, which factors in young blood mediate cognitive improvements in old mice is incompletely understood. Here, we show that serum extracted from the blood of young but not old mice, when applied to neurons transdifferentiated from human embryonic stem cells, directly increased dendritic arborization, augmented synapse numbers, doubled dendritic spine-like structures, and elevated synaptic N-methyl-d-aspartate (NMDA) receptors, thereby increasing synaptic connectivity. Mass spectrometry revealed that thrombospondin-4 (THBS4) and SPARC-like protein 1 (SPARCL1) were enriched in serum from young mice. Strikingly, recombinant THBS4 and SPARCL1 both increased dendritic arborization and doubled synapse numbers in cultured neurons. In addition, SPARCL1 but not THBS4 tripled NMDA receptor-mediated synaptic responses. Thus, at least two proteins enriched in young blood, THBS4 and SPARCL1, directly act on neurons as synaptogenic factors. These proteins may represent rejuvenation factors that enhance synaptic connectivity by increasing dendritic arborization, synapse formation, and synaptic transmission.Keywords
Funding Information
- HHS | NIH | National Institute of Mental Health (MH052804)
- NIMH (MH092931)
- Canadian HIV Trials Network, Canadian Institutes of Health Research (MFE-141209)
This publication has 63 references indexed in Scilit:
- Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRHNature, 2013
- Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4Nature, 2013
- Adhesion-modulating/matricellular ECM protein families: A structural, functional and evolutionary appraisalMatrix Biology, 2012
- The ageing systemic milieu negatively regulates neurogenesis and cognitive functionNature, 2011
- Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARCProceedings of the National Academy of Sciences of the United States of America, 2011
- Gabapentin Receptor α2δ-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS SynaptogenesisCell, 2009
- Synapses are lost during aging in the primate prefrontal cortexNeuroscience, 2007
- Changes in the structural complexity of the aged brainAging Cell, 2007
- Neural plasticity in the ageing brainNature Reviews Neuroscience, 2006
- Cellular Internalization and Degradation of Thrombospondin-1 Is Mediated by the Amino-terminal Heparin Binding Domain (HBD)Published by Elsevier BV ,1997