Synapse-boosting factors in young blood

Synapse-boosting factors in young blood

Cognitive aging is driven by changes in systemic factors circulating in blood, according to one hypothesis. Studies supporting this hypothesis have found that transfusing the blood of young mice into old mice—a process called parabiosis—increases brain synaptic connectivity and reverses learning and memory deficits.

Putative factors in the blood of young mice have been reported, but whether these factors act directly on the brain or through indirect mechanisms remains unclear. Researchers report that unlike blood serum from 12- to 15-month-old mice, serum from 15-day-old mice enhanced neuronal dendrite branching, synapse numbers, neurotransmitter release, and N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic function in cultured neurons differentiated from human embryonic stem cells.

Electrophysiological experiments revealed that serum from young mice directly acted on human neurons and boosted their synaptic connectivity, unlike serum from old mice. Adding young serum to neurons that had been cultured in old serum increased synaptic function, whereas adding old serum to neurons cultured in young serum slightly reduced synaptic function, suggesting a causal role for synapse-promoting factors in young serum rather than a role for synapse-inhibiting factors in old serum.

Using tandem mass spectrometry, the authors identified 2 proteins—thrombospondin 4 (THBS4) and SPARC-like protein 1 (SPARCL1)—that were enriched in young serum and whose recombinant versions recapitulated many of the synapse-promoting effects of young serum. Both proteins increased synaptic connectivity, whereas SPARCL1, but not THBS4, enhanced NMDAR synaptic responses.

According to the authors, young blood may contain multiple synapse-promoting factors, whose gradual loss might lead to cognitive aging and decline.