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https://www.nature.com/articles/nature22067
- Nature 544, 488–492 (27 April 2017)
- doi:10.1038/nature22067
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- Received:
- Accepted:
- Published online:
Abstract
Ageing
drives changes in neuronal and cognitive function, the decline of which
is a major feature of many neurological disorders. The hippocampus, a
brain region subserving roles of spatial and episodic memory and
learning, is sensitive to the detrimental effects of ageing at
morphological and molecular levels. With advancing age, synapses in
various hippocampal subfields exhibit impaired long-term potentiation1,
an electrophysiological correlate of learning and memory. At the
molecular level, immediate early genes are among the synaptic plasticity
genes that are both induced by long-term potentiation2,3,4 and downregulated in the aged brain5,6,7,8. In addition to revitalizing other aged tissues9,10,11,12,13, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters14,15,16,
although the identities of specific cognition-promoting factors or
whether such activity exists in human plasma remains unknown17.
We hypothesized that plasma of an early developmental stage, namely
umbilical cord plasma, provides a reservoir of such plasticity-promoting
proteins. Here we show that human cord plasma treatment revitalizes the
hippocampus and improves cognitive function in aged mice. Tissue
inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched
in human cord plasma, young mouse plasma, and young mouse hippocampi,
appears in the brain after systemic administration and increases
synaptic plasticity and hippocampal-dependent cognition in aged mice.
Depletion experiments in aged mice revealed TIMP2 to be necessary for
the cognitive benefits conferred by cord plasma. We find that systemic
pools of TIMP2 are necessary for spatial memory in young mice, while
treatment of brain slices with TIMP2 antibody prevents long-term
potentiation, arguing for previously unknown roles for TIMP2 in normal
hippocampal function. Our findings reveal that human cord plasma
contains plasticity-enhancing proteins of high translational value for
targeting ageing- or disease-associated hippocampal dysfunction.
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