Accumulating evidence suggests that both intrinsic and extrinsic factors shape the function of neural circuits within specific substructures of the adult brain. A primary goal of my laboratory is to identify mechanisms by which influences outside the CNS 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 immune system. As such, another arm of the laboratory will focus on characterizing the extent to which blood-borne factors altered in the course of normal aging 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 a new frontier in neuroscience: how the brain’s learning and memory (formation, consolidation) circuits are shaped by systemic influences and the extent to which this plays a role in disease.
Castellano JM. Blood-Based Therapies to Combat Aging. Gerontology. 2019;65(1):84-89. doi: 10.1159/000492573. Epub 2018 Sep 7. PubMed PMID: 30196300.
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.
You leave your car in a vast, crowded parking lot, and when you return, you have no idea where it is. The ensuing search is frustrating, time-consuming and a little embarrassing.
That experience occurs more frequently as we get older, because the functions of the part of the brain that encodes spatial and episodic memories — the hippocampus — decline with age.
Blood from human infants appears to improve learning and memory in older mice, a new study shows. The research is the latest in a new field of inquiry, where scientists are looking to see if blood from the very young can rejuvenate the old.
A new study hints that young blood may harbor clues to a “fountain of youth” for older brains.
Researchers say blood from human umbilical cords appears to have helped reverse memory loss in aging mice.
The findings suggest that something in young blood is important in maintaining mental acuity.
Decades ago, scientists surgically attached pairs of rats to each other and noticed that old rats tended to live longer if they shared a bloodstream with young rats.
It was the beginning of a peculiar and ambitious scientific endeavor to understand how certain materials from young bodies, when transplanted into older ones, can sometimes improve or rejuvenate them.
Dementia patients have been offered hope that their memory could be repaired after scientists showed that injecting blood from the umbilical cords of human babies restores brain function.
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.
(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
- 2018 BrightFocus Foundation Grant
- 2018 Friedman Brain Institute Scholar Award
- 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/R00 Pathway to Independence Award (NIA/NIH)
K99/R00 Pathway to Independence Award, “Regulation of hippocampal plasticity and learning and memory by a bloodborne rejuvenation factor”
Meet the Team
Joseph Castellano, Ph.D.
Role: Principal Investigator
As a graduate student in David Holtzman’s group at Washington University in St. Louis, I studied how the strongest genetic risk factor for Alzheimer’s disease influences metabolism of the pathogenic amyloid beta peptide from brain interstitial fluid. I used in vivo microdialysis to show in behaving mice that clearance of this peptide is impeded by the presence of APOE4 whereas clearance in the context of more protective forms is faster. During my postdoctoral training in Tony Wyss-Coray’s group at Stanford University, I became engrossed in characterizing factors in the periphery that reverse features of brain aging, finding that systemic umbilical cord plasma treatment revitalizes hippocampal function in aged mice. My laboratory now focuses on characterizing the activity of blood-borne proteins like TIMP2 that mediate long-range effects on circuits in the brain in the context of Alzheimer’s disease.
Ana Catarina Ferreira
Role: Postdoctoral Fellow
Catarina received her PhD in Health Sciences in 2017 from the School of Medicine at the University of Minho in Portugal. During this time, she focused on the identification of novel mechanisms that regulate different forms of neural plasticity, specifically the generation of new neural cells in the adult brain and the implications of this plasticity in the overall maintenance of brain homeostasis and behavior. Catarina demonstrated that the iron-traffic protein lipocalin-2 (LCN2) is required to control quiescent and active states of adult neural stem cells for proper adult cell genesis, ultimately regulating cognitive function. As a postdoc in the Castellano lab, Catarina is focused on understanding how activity of the youth-associated blood-born factor TIMP2 shapes brain circuits linked to learning and memory and understanding this action in the context of Alzheimer’s disease. Outside the lab, Catarina enjoys reading, spending time with friends, and traveling.
Role: Associate Researcher/Lab Manager
Danielle received her B.S. in Biology in 2016 from the Honor’s College at the College of Charleston in South Carolina. During this time and following graduation, she worked in Dr. Peter Kalivas’s lab investigating pathophysiology and behavior in rodent models of drug addiction at the Medical University of South Carolina (MUSC). While at MUSC, Danielle also conducted clinical trials investigating cessation methods for tobacco use disorder as a Project Coordinator for Dr. Erin McClure. Outside of the lab, Danielle enjoys surfing, travelling, and spending time with friends and her cat, Taco.
Role: Associate Researcher/Lab Manager
Jeffrey received his B.S. in Neural Science in 2019 from New York University. During his undergraduate career, he worked in Dr. Eric Klann’s laboratory studying the molecular mechanisms of translational control and their role in various cognitive disorders. His bachelor’s thesis sought to characterize the role of cap-dependent translation in cortico-striatal circuitry in a mouse model of Fragile X Syndrome. While in the lab, Jeffrey hopes to further his interest in studying neurological diseases including Alzheimer’s. Apart from research, Jeffrey enjoys exploring biking around the city and spending time with friends.
Role: Masters Student
Yihang received her B.S. in biology in 2018 from Wuhan University in China. During her undergraduate years, her study focused on conducting mouse surgeries to identify the neurocircuits associated with the hippocampus using different types of virus vectors. Her bachelor thesis is around identifying the monosynaptic input of the excitatory neurons of the amygdala on a whole-brain basis. As a new masters student here at Mount Sinai, her interest is to take what she learned before and direct it in a way that’s more focused on neurodegenerative diseases like Alzheimer’s. Apart from scientific research, she also enjoys exploring New York’s numerous museums and Broadway shows and reading a good book with her cat Dulcinea purring on the lap.
Role: Research Intern
Annie received her B.A. in Biology and Psychology from University of California, Berkeley, and she is currently a Master’s student at Columbia University. During her undergraduate career, she worked in Dr. Alison Harvey’s clinical sleep lab studying sleep deprivation and circadian tendency towards eveningness and their impact on cognition, with an emphasis on memory. She also worked in Dr. Lucia Jacobs’ lab studying the role of olfaction in spatial memory. Annie hopes to further her interest in learning and memory in the context of Alzheimer’s disease in the Castellano lab. Outside of school and lab, she enjoys hiking, kickboxing, and reading, and she is an avid traveler who hopes to visit all 7 continents.
Ambar Kleinbort, Barnard College/Columbia University
Role: Undergraduate Research Intern
Lab Member: May 2018 – September 2018
Volunteer, graduate student, and postdoctoral positions are available to study the interactions between blood/immune system and the brain in the setting of aging and neurodegenerative disease (see Castellano, J.M., Nature, 2017 for our recent work). The Castellano laboratory is also a member of the Ronald Loeb Center for Alzheimer’s disease.
Successful candidates will join an energetic team that conducts a range of sophisticated techniques, including parabiosis, in vivo microdialysis, and next-generation sequencing. The lab also employs conventional methodologies, including confocal microscopy, molecular cloning, viral-mediated gene transfer, and behavioral studies to understand processes of synaptic plasticity, as well as memory consolidation and retention in rodent models of aging and Alzheimer’s disease.
The Castellano laboratory at the Icahn School of Medicine at Mount Sinai is looking for a talented Postdoctoral Fellow to join our group! Our lab is in the Department of Neuroscience and a member of the Friedman Brain Institute and Ronald Loeb Center for Alzheimer’s disease.
Successful candidates will join a new team that conducts a range of sophisticated techniques, including parabiosis, in vivo microdialysis, and next-generation sequencing. We also employ conventional methodologies, including confocal microscopy, molecular cloning techniques, viral-mediated gene transfer, and behavioral studies to understand processes of synaptic plasticity and memory in rodent models of aging and Alzheimer’s disease. We are seeking a creative, highly motivated individual with a recent Ph.D. (less than one year) in Neuroscience or a related field who will pursue a funded project related to APOE risk and immune interactions regulating brain health. Expertise in molecular biology, rodent handling, microscopy, and basic biochemical techniques is required and experience in next-generation sequencing (bulk or single-cell) is preferred but not required. Interested candidates should send a cover letter, a CV (include details of technical expertise), and the contact information of 3 referees to Joseph.Castellano@mssm.edu. Click here to apply through Mount Sinai.
We are actively seeking current undergraduates or recently graduated students who are motivated and excited to deepen their laboratory experience. Mentored lab experiences are available for students at this level to learn new techniques, work on a hypothesis-driven project, and to enhance critical reasoning and technical skills in preparation for graduate or medical school. Interested candidates should send a CV (include details of technical expertise) along with contact information of mentors from previous laboratory experiences. Please send directly to Joseph.Castellano@mssm.edu.
We are accepting students for rotations for the Fall! Masters student positions are also available. Please email Joseph.Castellano@mssm.edu to inquire.
Human umbilical cord plasma proteins revitalize hippocampal function in aged mice
Joseph M. Castellano, Kira I. Mosher, Rachelle J. Abbey, Alisha A. McBride, Michelle L. James, Daniela Berdnik, Jadon C. Shen, Bende Zou, Xinmin S. Xie, Martha Tingle, Izumi V. Hinkson, Martin S. Angst & Tony Wyss-Coray
Nature 544, 488–492 (27 April 2017) doi:10.1038/nature22067
Received 19 November 2015 Accepted 14 March 2017 Published online 19 April 2017