David M Holtzman, MD
Andrew B. and Gretchen P. Jones Professor and Chairman of the Department of Neurology
1983 Graduation with highest distinction. Phi Beta Kappa, AOA Northwestern University
1992 S. Wier Mitchell Award, best manuscript, Junior member, American Academy of Neurology
1993 National Down Syndrome Scholar
1994 Culpeper Foundation Medical Science Scholar
1995 Paul Beeson Physician Faculty Scholar Award (American Federation for Aging Research)
2001 Charlotte and Paul Hagemann endowed Professorship, Dept. Neurology, Washington University
2003 Potamkin Award for Alzheimer’s Disease Research, American Academy of Neurology
2004 Elected American Society for Clinical Investigation
2004 MERIT award-NIA
2006 MetLife Award for Alzheimer’s Disease Research; 2002, MetLife award for promising AD research
2008 Member, Institute of Medicine, National Academy of Sciences
2010 Alumni Merit Award, Northwestern University Feinberg School of Medicine
2011 Member, National Advisory Council, NINDS
2012 PhRMA, Research and Hope Award
2013 Chancellor’s Award for Innovation and Entrepreneurship
2015 Carl and Gerty Cori Faculty Achievement Award, Washington University
2015 President elect, American Neurological Association
2016 Member, NIH Council of Councils
My lab is interested in understanding the pathogenesis of Alzheimer’s disease and other neurodegenerative disorders. Abundant evidence suggests a central role for the amyloid-β (Aβ) peptide in Alzheimer’s disease (AD) pathogenesis. Changes in Aβ conformation from forms with predominantly random coil/alpha helix to both soluble and insoluble forms with high beta-sheet content appears to be a key event in AD. We are interested in developing a better understanding of Aβ metabolism in the CNS. Some of our studies are trying to understand the role of endogenous (e.g. apoE) and exogenous Aβ binding molecules (anti-Aβ antibodies) in regulating Aβ metabolism and toxicity. ApoE genotype is the most important genetic risk factor for AD and understanding how it contributes to AD pathogenesis is likely to provide key insights into the cause of and potentially treatments for AD. We use a variety of transgenic and knockout mice as well as unique biological assays (e.g. brain microdialysis to measure proteins and other metabolites) to study mechanisms leading to AD pathology and cerebral amyloid angiopathy (CAA). Over the past several years, we have found that a major regulator of Aβ metabolism is synaptic activity. We have found that synaptic activity and synaptic vesicle release is coupled with Aβ release from the synapse in vivo. This finding has important implications for understanding why Aβ deposition occurs in specific brain regions as well as has important implications for development of novel treatments. It is also likely relevant to how the sleep/wake cycle regulates Aβ levels and deposition. We are actively pursuing the relationship between sleep and neurodegenerative disease. Interestingly, there is an increased risk of AD in individuals with high glucose and diabetes. We are following up this link by study whether changes in glucose and insulin acutely and chronically impact on AD-related protein metabolism in the brain. In addition to studies on Aβ and apoE metabolism, we have also been studying the metabolism of tau protein. Specifically, we have been able to assess extracellular tau by in vivo microdialysis and are interested in understanding the regulation of tau metabolism and how to block tau aggregation and its spread within the CNS. In human studies, it has been shown that by the time of clinical onset of AD, there is already substantial buildup of amyloid in the brain along with neurofibrillary pathology, neuronal cell death, and synaptic loss. It is estimated that AD pathology begins to build up ~10-15 years prior to onset of dementia. Thus, a major goal in the field is to discover antecedent biomarkers for AD to detect AD pathology prior to symptom onset so that treatments can be used to prevent and delay dementia. We have been assessing CSF and plasma samples from human subjects at the Washington University ADRC and have found that decreased CSF Aβ42 and increased tau, VILIP-1, neurogranin, and YKL-40 are harbingers of cognitive decline in cognitively normal elderly. We are following up on these findings as well as utilizing traditional methods such as ELISA as well as mass spectrometry coupled with neuroimaging to find new biomarkers.
Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, Mackey B, Olney J, McKeel D, Wozniak D, Paul SM (2000). Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 97:2892-2897.
DeMattos RB, Bales KR, Cummins DJ, Dodart J-C, Paul SM, Holtzman DM. (2001) Peripheral anti-A? antibody alters CNS and plasma A? clearance and decreases brain A? burden. Proceedings of the National Academy of Science USA98: 8850-8855:10.1073/pnas.151261398.
DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM. (2002) Brain to plasma amyloid-? efflux: A measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 295:2264-2267.
Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM. (2002) Immunization reverses memory deficits without reducing A? burden in Alzheimer’s disease model. Nature Neuroscience 5:452-457.
Brendza RP, Bacskai BJ, Cirrito JR, Simmons KA, Skoch JM, Klunk WE, Mathis CA, Bales KR, Paul SM, Hyman BT, Holtzman DM. (2005) Anti-A? antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. Journal of Clinical Investigation 115:428-433.
Cirrito JR, Yamada KA, Finn MB, SloviterRS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. (2005) Synaptic activity regulates interstitial fluid amyloid-b levels in vivo. Neuron 48(6):913-922.
WahrleSE, Jiang H, Parsadanian M, Kim J, Li A, KnotenA, Jain S, Hirsch-Reinshagen V, Wellington CL, BalesKR, Paul SM, Holtzman DM. (2008) Over-expression of ABCA1 in the PDAPP mouse model of Alzheimer’s disease markedly reduces amyloid deposition J. Clin. Invest. 188(2):671-682. PMCID: PMC2200302
Cirrito JR, Kang J-E, LeeJ, Stewart FR, Verges D, Silverio LM Bu G, MennerickS, Holtzman DM. (2008) Endocytosis is required for synaptic activity-dependent release of amyloid-b in vivo. Neuron 58:42-51. PMCID: PMC2390913
Brody DL, Magnoni S, SchwetyeKE, Spinner M, Esparza TJ, Stocchetti N, Zipfel GJ, Holtzman DM. (2008) Amyloid-? Dynamics Correlate with Neurological Status in the Injured Human Brain Science 321:1221 –1224. PMCID: PMC2577829
Kim J, Castellano JM, Jiang H, Basak JM, 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 Abeta clearance. Neuron. 2009 Dec 10;64(5):632-44. PMCID: PMC2787195
Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. (2009) Amyloid- ? Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle. Science. 326:1005-1008. PMCID:PMC278983
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-? Peptide Clearance. Science Translational Medicine 29;3(89):89ra57. PMCID: PMC3192364
Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee JM, Holtzman DM. Neuronal activity regulates the regional vulnerability to amyloid-? deposition. Nat Neurosci. 2011 14(6):750-6. PMCID: PMC3102784
Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, Holmes BB, Binder LI, Mandelkow EM, Diamond MI, Lee VM, Holtzman DM. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci. 2011 Sep 14;31(37):13110-7. PMCID: PMC4299126
Roh JH, HuangY, BeroAW, KastenT, StewartFR, BatemanRJ, Holtzman DM. Disruption of the sleep-wake cycle and diurnal fluctuation of amyloid-? in mice with Alzheimer’s disease pathology. Science Translational Medicine 2012 Sep 5;4(150):150ra122. PMCID: PMC3654377
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
Yamada K, Holth JK, Liao F, Stewart FR, Mahan TE, Jiang H, Cirrito JR, Patel TK, Hochgräfe K, Mandelkow EM, Holtzman DM. Neuronal activity regulates extracellular tau in vivo. J Exp Med. 2014 10;211(3):387-93. PMCID: PMC3949564
Roh JH, Jiang H, Finn MB, Stewart FR, Mahan TE, Cirrito JR, Heda A, Snider BJ, Li M, Yanagisawa M, de Lecea L, Holtzman DM. Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer’s disease. J Exp Med. 2014 Dec 15;211(13):2487-96. doi: 10.1084/jem.20141788. PMCID: PMC4291528
Macauley SL, Stanley M, Caesar EE, Yamada SA, Raichle ME, Perez R, Mahan TE, Sutphen CL, Holtzman DM. Hyperglycemia modulates extracellular amyloid-? concentrations and neuronal activity in vivo. J Clin Invest. 2015 May 4. pii: 79742. doi: 10.1172/JCI79742. PMCID: PMC4497756
Yanamandra K, Jiang H, Mahan TE, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Annals Clin. Transl. Neurology 2015 Article first published online : 23 JAN 2015, DOI: 10.1002/acn3.176 PMCID: PMC4369277
Ulrich JD, Ulland TK, Colonna M, Holtzman DM. Elucidating the Role of TREM2 in Alzheimer’s Disease.
Neuron. 2017 Apr 19;94(2):237-248. doi: 10.1016/j.neuron.2017.02.042. Review. PMID: 28426958
Yanamandra K, Patel TK, Jiang H, Schindler S, Ulrich JD, Boxer AL, Miller BL, Kerwin DR, Gallardo G, Stewart F, Finn MB, Cairns NJ, Verghese PB, Fogelman I, West T, Braunstein J, Robinson G, Keyser J, Roh J, Knapik SS, Hu Y, Holtzman DM. Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy. Sci Transl Med. 2017 Apr 19;9(386). pii: eaal2029. doi: 10.1126/scitranslmed.aal2029. PMID: 28424326
Ising C, Gallardo G, Leyns CEG, Wong CH, Stewart F, Koscal LJ, Roh J, Robinson GO, Remolina Serrano J, Holtzman DM.
AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy.
J Exp Med. 2017 Apr 17. pii: jem.20162125. doi: 10.1084/jem.20162125. [Epub ahead of print] PMID: 28416651
Neurologist-in-Chief, Barnes-Jewish Hospital
Charlotte and Paul Hagemann Professor of Neurology
Andrew B. and Gretchen P. Jones Professor of Neurology
Dr. Holtzman attended the Honors Program in Medical Education at Northwestern University receiving his B.S. (1983) and M.D. (1985). He did medical internship followed by Neurology residency at UCSF from 1985-1989. He then did post-doctoral research training in the lab of William C. Mobley, MD, PhD, at UCSF from 1989-1994. At UCSF, he also established the Memory and Cognitive Disorders Clinic and was an Assistant Professor from 1991-1994. He moved to his own laboratory at Washington University in December of 1994. He was named as Associate Professor of Neurology in 2001, Professor in November of 2002, and as the Andrew and Gretchen Jones Professor and head of the Department of Neurology in October 2003. In addition to his laboratory, administrative, and teaching duties, Dr. Holtzman is involved in clinical and research activities at the Washington University Alzheimer’s Disease Research Center and is scientific director of the Hope Center for Neurological Disorders. Past honors include being the recipient of a Paul Beeson Physician Faculty Scholar Award in Aging Research, recipieint of the Potamkin Prize from the American Academy of Neurology for research on Alzheimer’s (2003), election to the American Society for Clinical Investigation (2004), receiving a MERIT award from the NIA (2004), being a recipient of the MetLife award on Alzheimer’s disease (2006), election to the Institute of Medicine of the National Academy of Sciences (2008), being a recipient of the alumni merit award from Northwestern Feinberg School of Medicine (2010), being appointed to the National Advisory Council of the NINDS (2011), a recipient of the Chancellor’s Award for Innovation and Entrepreneurship (2013), being elected Fellow of the AAAS (2014), a recipient of the Carl and Gerty Cori Faculty Achievement Award at Washington University (2015), being elected president-elect of the American Neurological Association (2015), and being appointed to the NIH Council of Councils (2016).