Gan KJ, Südhof TC. Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment. Proc Natl Acad Sci U S A. 2019 Jun 18;116(25):12524-12533. Epub 2019 Jun 3 PubMed.

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  1. It is exciting to read a paper focusing on potential mechanistic aspects of young plasma-mediated regeneration of the aging brain. In these elegantly designed studies, the focus lies on how synapse generation and synaptic function in human ES-cell-derived neurons are impacted by serum from young and aged mice. The authors clearly demonstrate a direct beneficial effect of young mouse plasma-derived serum on neurons, even in the absence of glia cells.

    Interestingly, not only was young serum beneficial on its own, but it was able to overcome effects of aged serum when it was added after cells were 35 days in vitro and miniature excitatory post-synaptic currents were recorded at DIV42. Conversely, aged serum had the opposite effect, suggesting that young serum might also make the neurons more resistant to detrimental effects. Using TMT Mass Spec the authors identified THBS4 and SPARCL1 as specific factors enriched in young serum and lacking in aged serum as mediators of beneficial effects on synapse formation and function.

    Overall, the study validates that protein factors in serum derived from young, but not aged mice can affect critical neuronal functions that are impaired in aging. This supports findings by us at Alkahest (unpublished data) and others (Villeda et al., 2011; Villeda et al., 2014; Castellano et al., 2017) that young plasma or specific fractions and proteins can overcome aging associated deficits.

    References:

    Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011 Sep 1;477(7362):90-4. PubMed.

    Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, Wabl R, Udeochu J, Wheatley EG, Zou B, Simmons DA, Xie XS, Longo FM, Wyss-Coray T. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014 Jun;20(6):659-63. Epub 2014 May 4 PubMed.

    Castellano JM, Mosher KI, Abbey RJ, McBride AA, James ML, Berdnik D, Shen JC, Zou B, Xie XS, Tingle M, Hinkson IV, Angst MS, Wyss-Coray T. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature. 2017 Apr 19; PubMed.

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