David M. Holtzman

David M. Holtzman is an American neurologist and neuroscientist known for his work exploring the biological mechanisms underlying neurodegeneration, with a focus on Alzheimer's Disease. Holtzman is Professor and Chair of the Department of Neurology, Scientific Director of the Hope Center for Neurological Disorders, and Associate Director of the Knight Alzheimer's Disease Research Center at Washington University School of Medicine in St. Louis, Missouri. Holtzman's lab is known for uncovering how apoE4 contributes to Alzheimer's disease as well as how synaptic activity and sleep modulate amyloid beta and tau levels in the brain. His work has also uncovered the contributions of microglia to amyloid beta and tau pathology in neurodegeneration.

David M. Holtzman
Born
St. Louis, Missouri
NationalityAmerican
Alma materNorthwestern University
University of California, San Francisco
Known forMechanisms underlying neurodegeneration, including role of apoE, amyloid beta, tau, and TREM2 in pathogenesis of Alzheimer’s disease
AwardsPaul Beeson Physician Faculty Scholar Award, Potamkin Award for Alzheimer’s Disease Research, MetLife Award for Alzheimer’s Disease, Elected Fellow of AAAS, Member, National Academy of Medicine
Scientific career
FieldsNeuroscience
InstitutionsWashington University School of Medicine

Early life and education

Holtzman was born in St. Louis, Missouri.[1] Holtzman's mother was a nurse, his father was an architectural engineer, and he was the oldest of three children in his family.[1] Inspired to become a physician from a young age, Holtzman pursued a six-year combined Bachelor's and Medical Degree at Northwestern University in Evanston, Illinois. He obtained his Bachelors of Science in Medical Education in 1983 and his Medical Degree in 1985 at the age of 23.[1]

After completing his MD, Holtzman pursued a residency in Neurology at the University of California, San Francisco (UCSF) from 1985 to 1989.[2] Following his residency, he completed his postdoctoral research under the mentorship of William C. Mobley at UCSF from 1989 to 1994.[2] His postdoctoral research focused on developing mouse models of neurodegeneration as well as elucidating the role neurotrophins play in modulating neuronal activity.[3][4] While completing his postdoctoral work, Holtzman also became an Adjunct Assistant Professor in the Department of Neurology at UCSF.[2] He also founded the Memory and Cognitive Disorders clinic at UCSF.[5]

Career and research

In 1994, Holtzman became an Assistant Professor at Washington University in St. Louis where he became the principal investigator of the Holtzman Lab, in addition to teaching and clinical activities.[5] By 2002, Holtzman was promoted to Associate Professor of Neurology, and by 2003, he was promoted to Full Professor in the Departments of Neurology and Developmental Biology at Washington University.[6] In 2003, he also became the Chairman of the Department of Neurology, and in 2015 he became the Scientific Director of the Hope Center for Neurological Disorders.[6]

Holtzman is currently Professor and Chair of Neurology, scientific director of the Hope Center for Neurological Disorders, and Associate Director of the Knight Alzheimer's Disease Research Center at Washington University School of Medicine.[7]  The Holtzman Lab is dedicated to exploring the biological mechanisms underlying neurodegeneration.[8] Holtzman's work has uncovered mechanisms by which apoE, amyloid beta, and tau metabolism are implicated in neurodegeneration in the context of Alzheimer's Disease.[8] Holtzman is also a co-founder of C2N Diagnostics, LLC. Holtzman and his former trainee, Randall Bateman, developed C2N Diagnostics in 2007 with the goal of increasing the understanding the molecular mechanisms underlying neurological diseases through measurements of concentration and metabolism of CNS-derived biomolecules.[9][10]

Apolipoprotein E and Alzheimer's Disease

Holtzman and his lab have made major contributions to our understanding of the role of apoE in AD pathogenesis.[11] Both the ε4 and ε2 APOE alleles increase the risk of developing AD, with an approximately 12-fold AD risk for those with two copies of ε4 allele.[8] Holtzman's Lab has shown that apoE contributes to AD susceptibility and pathogenesis by its modulation of Aβ clearance and aggregation. Specifically, they have found that different isoforms of apoE have differential effects on soluble Aβ clearance.[12] When apoE binding proteins, such as LDLR, are up-regulated to decrease apoE, they found enhanced Aβ clearance and decreased Aβ depositions in the brains of mice.[12] They also found that apoE is implicated in neurodegeneration through aberrant activation of the brain's innate immune cells, microglia.[13][10]

Amyloid beta and synaptic activity

Using novel tools, such as in vivo microdialysis in combination with electrophysiology, Holtzman and his team were able to discern that synaptic activity influences Aβ levels in the brain.[14] They also found that Aβ deposition is brain region dependent, specifically correlating with regions involved in the default mode network. These findings suggest that increased metabolic demands and activity levels lead to higher soluble Aβ loads in these brain regions involved in the default mode network.[15]

Immunotherapeutic approaches for Alzheimer's Disease

The Holtzman Lab has shown the therapeutic benefits of antibody therapies in the context of AD. In 2001, Holtzman and his team published a foundational paper showing that administration of the anti-Aβ antibody (m266) in mice changes the equilibrium of Aβ across the CNS and blood plasma leading to increased Aβ sequestration in plasma which reduces the burden of Aβ in the brain.[16] This antibody, m266, was licensed to Eli Lilly and humanized.  Using the humanized anti-Aβ antibody, Solanezumab, Eli Lilly began a series of clinical trials to discern the therapeutic potential of anti-Aβ immunotherapy in humans with AD. Solanezunmab treatment did not meet the primary endpoint of the clinical trials in mild AD, however, a clinical trial known as A4 in “presymptomatic” AD is still ongoing.[17] Holtzman's lab has also focused on anti-tau immunotherapeutic approaches to treating AD, and this approach is now in phase II clinical trials following licensing of an anti-tau antibody his lab developed with AbbVie.[18]

Sleep and Alzheimer’s Disease

The Holtzman lab has made important advances in our understanding of how sleep cycles influence Aβ concentrations in the brain interstitial fluid and Cerebrospinal Fluid. They found that Aβ and tau are higher during wakefulness and lower during sleep, and that these differences in Aβ and tau dynamics are driven by synaptic activity differences and orexin signaling.[19][20] Following this work, Holtzman and his team found that once Aβ has been deposited, it results in sleep disruptions and further Aβ aggregation in a positive feedback loop promoting increased pathology.[19] They also found that sleep cycles are implicated in the release of extracellular tau and that less NREM sleep is linked to increased tau pathology.[21]

Awards and honors
  • 1995 Paul Beeson Physician Faculty Scholar Award (American Federation for Aging Research)[22]
  • 2001 Charlotte and Paul Hagemann endowed Professorship, Dept. Neurology, Washington University [23]
  • 2002, MetLife award for promising AD research
  • 2003 Potamkin Award for Alzheimer's Disease Research, American Academy of Neurology[5]
  • 2004 Elected American Society for Clinical Investigation[2]
  • 2004 MERIT award-NIA[24]
  • 2006 MetLife Award for Alzheimer's Disease Research[25]
  • 2008 Member, Institute of Medicine (now National Academy of Medicine), National Academy of Sciences[5]
  • 2010 Alumni Merit Award, Northwestern University Feinberg School of Medicine[5]
  • 2011 Member, National Advisory Council, NINDS
  • 2012 PhRMA, Research and Hope Award[26]
  • 2013 Chancellor's Award for Innovation and Entrepreneurship[27]
  • 2014 Elected Fellow of AAAS[28]
  • 2015 Carl and Gerty Cori Faculty Achievement Award, Washington University[29]
  • 2017 President, American Neurological Association[30]
  • 2018 Member, National Academy of Inventors[31]
  • 2019 Watanabe Prize in Translational Research, Indiana Clinical and Translational Sciences[32]

Select publications

  • Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, Lucey BP, Holtzman DM. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019 Feb 22;363(6429):880-884.[20]
  • Leyns CEG, Gratuze M, Narasimhan S, Jain N, Koscal LJ, Jiang H, Manis M, Colonna M, Lee VMY, Ulrich JD, Holtzman DM. TREM2 function impedes tau seeding in neuritic plaques. Nat Neurosci. 2019 Aug;22(8):1217-1222. doi: 10.1038/s41593-019-0433-0. PMCID:PMC6660358[33]
  • Liao F, Li A, Xiong M, Bien-Ly N, Jiang H, Zhang Y, Finn MB, Hoyle R, Keyser J, Lefton KB, Robinson GO, Serrano JR, Silverman AP, Guo JL, Getz J, Henne K, Leyns CE, Gallardo G, Ulrich JD, Sullivan PM, Lerner EP, Hudry E, Sweeney ZK, Dennis MS, Hyman BT, Watts RJ, Holtzman DM. (2018) Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation. J Clin Invest. 209(12):2149-56. PMCID: PMC3501350
  • Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao Z, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld CB, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM (2017) ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 2017 Sep 28;549(7673):523-527.[10]
  • Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, Wozniak DF, Marc, Diamond MI, Holtzman DM. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 2013 Oct 16;80(2):402-14. PMCID: PMC3924573[34]
  • Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee JM, Holtzman DM.  Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci. 2011 14(6):750-6.[35]
  • Castellano JM, Kim J, Stewart FR, Hong J, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM. (2011) Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance. Science Translational Medicine 29;3(89):89ra57. PMCID: PMC3192364[36]
  • Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. (2009) Amyloid- β  Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle. Science. 326:1005-1008. PMCID:PMC2789838[37]
  • Brody DL, Magnoni S, Schwetye KE, Spinner M, Esparza TJ, Stocchetti N, Zipfel GJ, Holtzman DM. (2008) Amyloid-β Dynamics Correlate with Neurological Status in the Injured Human Brain. Science 321: 1221 – 1224.[38]
  • Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. (2006) Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nature Medicine 12(7):856-861.[39]
  • DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM. (2002) Brain to plasma amyloid-β efflux:  A measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science 295:2264-2267.[40]

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  16. DeMattos, Ronald B.; Bales, Kelly R.; Cummins, David J.; Dodart, Jean-Cosme; Paul, Steven M.; Holtzman, David M. (2001-07-17). "Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease". Proceedings of the National Academy of Sciences of the United States of America. 98 (15): 8850–8855. Bibcode:2001PNAS...98.8850D. doi:10.1073/pnas.151261398. ISSN 0027-8424. PMC 37524. PMID 11438712.
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  34. Yanamandra, Kiran; Kfoury, Najla; Jiang, Hong; Mahan, Thomas E.; Ma, Shengmei; Maloney, Susan E.; Wozniak, David F.; Diamond, Marc I.; Holtzman, David M. (2013-10-16). "Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo". Neuron. 80 (2): 402–414. doi:10.1016/j.neuron.2013.07.046. ISSN 1097-4199. PMC 3924573. PMID 24075978.
  35. Bero, Adam W; Yan, Ping; Roh, Jee Hoon; Cirrito, John R; Stewart, Floy R; Raichle, Marcus E; Lee, Jin-Moo; Holtzman, David M (2011-05-01). "Neuronal activity regulates the regional vulnerability to amyloid-β deposition". Nature Neuroscience. 14 (6): 750–756. doi:10.1038/nn.2801. ISSN 1097-6256. PMC 3102784. PMID 21532579.
  36. Castellano, Joseph M.; Kim, Jungsu; Stewart, Floy R.; Jiang, Hong; DeMattos, Ronald B.; Patterson, Bruce W.; Fagan, Anne M.; Morris, John C.; Mawuenyega, Kwasi G.; Cruchaga, Carlos; Goate, Alison M. (2011-06-29). "Human apoE isoforms differentially regulate brain amyloid-β peptide clearance". Science Translational Medicine. 3 (89): 89ra57. doi:10.1126/scitranslmed.3002156. ISSN 1946-6242. PMC 3192364. PMID 21715678.
  37. Kang, Jae-Eun; Lim, Miranda M.; Bateman, Randall J.; Lee, James J.; Smyth, Liam P.; Cirrito, John R.; Fujiki, Nobuhiro; Nishino, Seiji; Holtzman, David M. (2009-11-13). "Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle". Science. 326 (5955): 1005–1007. Bibcode:2009Sci...326.1005K. doi:10.1126/science.1180962. ISSN 1095-9203. PMC 2789838. PMID 19779148.
  38. Brody, David L.; Magnoni, Sandra; Schwetye, Kate E.; Spinner, Michael L.; Esparza, Thomas J.; Stocchetti, Nino; Zipfel, Gregory J.; Holtzman, David M. (2008-08-29). "Amyloid-beta dynamics correlate with neurological status in the injured human brain". Science. 321 (5893): 1221–1224. Bibcode:2008Sci...321.1221B. doi:10.1126/science.1161591. ISSN 1095-9203. PMC 2577829. PMID 18755980.
  39. Bateman, Randall J.; Munsell, Ling Y.; Morris, John C.; Swarm, Robert; Yarasheski, Kevin E.; Holtzman, David M. (July 2006). "Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo". Nature Medicine. 12 (7): 856–861. doi:10.1038/nm1438. ISSN 1078-8956. PMC 2983090. PMID 16799555.
  40. DeMattos, Ronald B.; Bales, Kelly R.; Cummins, David J.; Paul, Steven M.; Holtzman, David M. (2002-03-22). "Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease". Science. 295 (5563): 2264–2267. Bibcode:2002Sci...295.2264D. doi:10.1126/science.1067568. ISSN 1095-9203. PMID 11910111. S2CID 37217460.
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