David M. Holtzman, M.D.

Andrew B. and Gretchen P. Jones Professor
Developmental Biology

Neurosciences Program
Molecular Cell Biology Program

Research Abstract:

A major interest in my lab is in understanding basic mechanisms underlying acute and chronic cell dysfunction in the CNS particularly as these mechanisms may relate to Alzheimer`s disease (AD) and injury to the developing brain.

There are two major areas of focus currently in my lab. Abundant evidence suggests a central role for both the amyloid-β (Aβ) peptide as well as the tau protein 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. Aβ brain microdialysis) to study mechanisms leading to AD pathology and cerebral amyloid angiopathy (CAA). Over the past several years, we have found that another 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 the possible connection between sleep, Aβ,, and AD. 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. We have found that certain antibodies to tau appear to decrease tau pathology in animal models of tauopathy, and we are trying to understand the mechanism(s) underlying the effects. 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, 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.

Selected Publications:

Macauley SL, Stanley M, Caesar EE, Yamada SA, Raichle ME, Perez R, Mahan TE, Sutphen CL, Holtzman DM. (2015) Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo. J Clin Invest. May 4. pii: 79742. doi: 10.1172/JCI79742

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. (2014) Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer`s disease. J Exp Med. Dec 15;211(13):2487-96. doi: 10.1084/jem.20141788.

Liao F, Hori Y, Hudry E, Bauer AQ, Jiang H, Mahan TE, Lefton KB, Zhang TJ, Dearborn JT, Kim J, Culver JP, Betensky R, Wozniak DF, Hyman BT, Holtzman DM. (2014) Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis. J. Neurosci. 34(21):7281-92

Yamada K, Holth JK, Liao F, Stewart FR, Mahan TE, Jiang H, Cirrito JR, Patel TK, Hochgrfe K, Mandelkow EM, Holtzman DM. (2014) Neuronal activity regulates extracellular tau in vivo. J Exp Med. Mar 10;211(3):387-93

Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, Wozniak DF, Diamond MI,Holtzman DM. (2013) Anti-Tau Antibodies that Block Tau Aggregate Seeding In Vitro Markedly Decrease Pathology and Improve Cognition In Vivo. Neuron 80: 402-414

Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, Shah A, Bu G, Frieden C, Holtzman DM. (2013) ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc Natl Acad Sci U S A. May 7;110(19):E1807-16. doi: 10.1073/pnas.1220484110. Epub 2013 Apr 25.

Musiek ES, Lim MM, Yang G, Bauer AQ, Qi L, Lee Y, Roh JH, Ortiz-Gonzalez X, Dearborn JT, Culver JP, Herzog ED, Hogenesch JB, Wozniak DF, Dikranian K, Giasson BI, Weaver DR, Holtzman DM, Fitzgerald GA. (2013) Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J Clin Invest. Dec;123(12):5389-400. doi: 10.1172/JCI70317. Epub 2013 Nov 25

Roh JH, Huang Y, Bero AW, Kasten T, Stewart FR, Bateman RJ, Holtzman DM. (2012) Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer`s disease pathology. Sci Transl Med. Sep 5;4(150):150ra122. doi: 10.1126/scitranslmed.3004291.

Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. (2009) Amyloid-beta Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle. Science 326:1005-1008.

Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM. (2009) Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Abeta Clearance. Neuron. 64:632-644.

Last Updated: 8/17/2015 10:58:40 AM

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