Projects

How do blood-borne factors influence the brain in the context of disease?

Conventional wisdom has held that the blood-brain barrier isolates the brain from the influence of the immune system and systemic environment. The concept that neural networks have a limited capacity for repair has also been challenged by recent progress in regenerative biology. With the discovery of novel immune interactions and anatomical pathways that link the peripheral and central compartments, opportunities have emerged to investigate blood/brain communication in attempts to develop new therapeutic targets for devastating disorders of the nervous system. Studies over the past decade have uncovered the regenerative capacity of aged tissues via factors in the blood (ref 1 for review; see Figure 1).

By surgically connecting young and aged mice via parabiosis, various groups working across disciplines have demonstrated that aged tissue is capable of revitalization simply by its exposure to cellular or molecular components of the young systemic milieu. Exposure to such factors via parabiosis or following transfer of young plasma revitalizes diverse processes within the brain, including vascularization, the birth of new neurons, synaptic plasticity and learning and memory (refs 1–4). I recently demonstrated that human plasma from an early developmental stage–umbilical cord plasma–contains proteins capable of revitalizing spatial learning and memory while increasing synaptic plasticity (ref 5). Moreover, we found that the youth-associated blood-borne factor, tissue inhibitor of metalloproteinases 2 (TIMP2), is necessary for the cognitive benefits conferred by cord plasma in aged mice. Neutralizing systemic pools of TIMP 2 using antibody-mediated approaches or through genetic ablation results in profound alterations in spatial memory in adult mice. While TIMP2-expressing hilar neurons are present at high levels in young mice, the number of these neurons declines profoundly with age. Systemic perturbation of TIMP2 results in functional changes at the level of synapses and, in some cases, at the level of gene transcription. A key focus of our group is to characterize how TIMP2 and related molecules act on circuits linked to learning and memory at various levels of analysis. We will answer fundamental questions of TIMP2 biology while also seeking the broader picture of how circulating molecules influence risk for disorders of the CNS and how aging shapes risk for these disorders. We will employ cutting-edge molecular and behavioral approaches to examine function while using next-generation ChIP-seq and RNA-seq approaches to unravel the complex interplay between systemic and central compartments.

References Cited

  1. Castellano JM, Kirby ED, Wyss-Coray T. Blood-Borne Revitalization of the Aged Brain. JAMA neurology. 2015;72(10):1191-4. doi: 10.1001/jamaneurol.2015.1616. PubMed PMID: 26237737; PubMed Central PMCID: PMC4867550.
  2. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011; 477(7362):90-4. Epub 2011/09/03. doi: 10.1038/nature10357. PubMed PMID: 2188 6162; PubMed Central PMCID: PMC3170097.
  3. Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014;20(6):659-63. Epub 2014/05/06. doi: 10.1038/nm.3569. PubMed PMID: 24793238.
  4. Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014;344(6184):630-4. Epub 2014/05/07. doi: 10.1126/science.1251141. PubMed PMID: 24797482; PubMed Central PMCID: PMC4123747.
  5. 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;544(7651):488-92. doi: 10.1038/nature22067. PubMed PMID: 28424512.