Accumulating evidence suggests that both intrinsic and extrinsic factors shape the function of neural circuits within certain substructures of the adult brain. A primary goal of my laboratory is to identify mechanisms by which blood-borne factors regulate brain function in the context of aging and disease. I recently demonstrated that the youth-associated blood-borne factor tissue inhibitor of metalloproteinases 2 (TIMP2) revitalizes hippocampal synaptic plasticity and cognition in aged mice. We are now actively exploring how TIMP2 acts on circuits linked to learning and memory at molecular, morphological, and transcriptional levels of analysis. Given that TIMP2’s role in the brain is relatively unknown, we are creating a variety of genetic tools to begin probing the precise mechanism by which TIMP2 and its putative binding partners act to shape synaptic plasticity processes. A related goal of my group is to clarify the link between risk factors for neurodegenerative disease and the systemic environment. As such, another arm of the laboratory will focus on characterizing the extent to which blood-borne factors altered in the course of the normal aging process play a role in the pathogenesis of Alzheimer’s disease or other neurodegenerative disorders. We leverage both systems “big data” approaches as well as conventional molecular, cellular, and behavioral methodologies to understand how the brain’s learning and memory circuits are shaped by systemic influences in the setting of disease.
Joseph M Castellano, PhD
Assistant Professor, Neuroscience
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.
Czirr E, Castello NA, Mosher KI, Castellano JM, Hinkson IV, Lucin KM, Baeza-Raja B, Ryu JK, Li L, Farina SN, Belichenko NP, Longo FM, Akassoglou K, Britschgi M, Cirrito JR, Wyss-Coray T. Microglial complement receptor 3 regulates brain Abeta levels through secreted proteolytic activity. J Exp Med. 2017;214(4):1081-92. doi: 10.1084/jem.20162011. PubMed PMID: 28298456; PubMed Central PMCID: PMC5379986.
Castellano JM, Palner M, Freeman GM, Li S, Nguyen A, Shen B, Stan T, Mosher KI, Chin F, de Lecea L, Luo J, Wyss-Coray T. In vivo assessment of behavioral recovery and circulatory exchange in the peritoneal parabiosis model. Scientific reports. 2016;6:29015. doi: 10.1038/srep29015. PubMed PMID: 27364522; PubMed Central PMCID: PMC4929497.
Zhang X, Wang H, Antaris AL, Li L, Diao S, Ma R, Nguyen A, Hong G, Ma Z, Wang J, Zhu S, Castellano JM, Wyss-Coray T, Liang Y, Luo J, Dai H. Traumatic Brain Injury Imaging in the Second Near-Infrared Window with a Molecular Fluorophore. Advanced materials. 2016;28(32):6872-9. doi: 10.1002/adma.201600706. PubMed PMID: 27253071; PubMed Central PMCID: PMC5293734.
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.
Shieh P, Dien VT, Beahm BJ, Castellano JM, Wyss-Coray T, Bertozzi CR. CalFluors: A Universal Motif for Fluorogenic Azide Probes across the Visible Spectrum. Journal of the American Chemical Society. 2015;137(22):7145-51. doi: 10.1021/jacs.5b02383. PubMed PMID: 25902190; PubMed Central PMCID: PMC4487548.
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 F, Wyss-Coray T. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014;20(6):659-63. doi: 10.1038/nm.3569. PubMed PMID: 24793238; PubMed Central PMCID: PMC4224436.
Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, Berkutzki T, Barnett-Itzhaki Z, Bezalel D, Wyss-Coray T, Amit I, Schwartz M. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science. 2014;346(6205):89-93. doi: 10.1126/science.1252945. PubMed PMID: 25147279; PubMed Central PMCID: PMC4869326.
Luo J, Nguyen A, Villeda SA, Zhang H, Ding Z, Derek L, Bieri G, Castellano JM, Beaupre G, Wyss-Coray T. Long-term cognitive impairments and pathological alterations in a mouse model of repetitive mild traumatic brain injury. Front Neurol. 2014;5:12. doi: 10.3389/fneur.2014.00012. PubMed PMID: 24550885; PubMed Central PMCID: PMC3912443.
Mak A CY, Pullinger CR, Tang LF, Wong JS, Deo RC, Schwarz J-M, Gugliucci A, Movsesyan I, Ishida BY, Chu C, Poon A, Kim P, Stock EO, Schaefer EJ, Asztalos BF, Castellano JM, Wyss-Coray T, Miller BL, Jane JP, Kwok P-Y, Malloy MJ. Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA neurology. 2014;71(10):1228-36. doi: 10.1001/jamaneurol.2014.2011. PubMed PMID: 25111166; PubMed Central PMCID: PMC4714860.
Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, Shah AR, Bu G, Frieden C, Holtzman DM. ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions. Proc Natl Acad Sci U S A. 2013;110(19):E1807-16. doi: 10.1073/pnas.1220484110. PubMed PMID: 23620513; PubMed Central PMCID: PMC3651443.
Ulrich JD, Burchett III JM, Restivo JL, Schuler DR, Verghese PB, Mahan TE, Landreth GE, Castellano JM, Jiang H, Cirrito JR, Holtzman DM. In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis. Molecular neurodegeneration. 2013;8:13. doi: 10.1186/1750-1326-8-13. PubMed PMID: 23601557; PubMed Central PMCID: PMC3640999.
Castellano JM, Deane R, Gottesdiener AJ, Verghese PB, Stewart FR, West T, Paoletti A, Kasper TR, DeMattos RB, Zlokovic BV, Holtzman DM. Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Abeta clearance in a mouse model of beta-amyloidosis. Proc Natl Acad Sci U S A. 2012;109(38):15502-7. doi: 10.1073/pnas.1206446109. PubMed PMID: 22927427; PubMed Central PMCID: PMC3458349.
Castellano JM, Kim J, Stewart FR, Jiang H, DeMattosRB, Patterson BW, FaganAM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM. Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med. 2011;3(89):89ra57. doi: 10.1126/scitranslmed.3002156. PubMed PMID: 21715678; PubMed Central PMCID: PMC3192364.
Verghese PB, Castellano JM, Holtzman DM. Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol. 2011;10(3):241-52. doi: 10.1016/S1474-4422(10)70325-2. PubMed PMID: 21349439; PubMed Central PMCID: PMC3132088.
Kim J, Castellano JM, Jiang H, Basak J, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM. Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance. Neuron. 2009;64(5):632-44. doi: 10.1016/j.neuron.2009.11.013. PubMed PMID: 20005821; PubMed Central PMCID: PMC2787195.
Role of Blood-borne Factors in Shaping Synaptic Plasticity in Diseases of Aging
Conventional wisdom has held that the brain is relatively isolated from the influence of the immune system and systemic environment as a result of the blood-brain barrier. 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 TIMP2 using antibody-mediated approaches or through genetic ablation results in profound alterations in spatial memory in adult mice. Moreover, while TIMP2 is expressed at high levels in hilar neurons within the dentate gyrus 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.
(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: 21886162; 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.
Funding & Awards
- Provost’s Undergraduate Research Award
- Outstanding Graduate for Excellence in Biochemistry Award
- Phi Beta Kappa
- Predoctoral Ruth L. Kirschstein National Research Service Award
- Conference Assistant Award, Keystone Conference (J5), Neurodegenerative Diseases
- Hope Center Award Finalist for Research in Translational Neuroscience
- 34th Annual James L. O’Leary Prize for Research in Neuroscience (Washington University)
- Jane Coffin Childs Postdoctoral Fellowship, Simons Foundation Fellow, accepted
- NIH Child Health Research Institute Postdoctoral fellowship, accepted
- Stanford Dean’s Postdoctoral Fellowship, awarded
- Postdoctoral Ruth L. Kirschstein National Research Service Award, awarded
- 2015 New Vision Award, Donor’s Cure Foundation, Charleston Conference on AD
- K99 Pathway to Independence Award (NIA/NIH)