David M. Holtzman, MD

Dr. Holtzman is the Andrew B. and Gretchen P. Jones Professor of Neurology and Molecular Biology & Pharmacology. He is also head of the Department of Neurology, the Associate Director of the Alzheimer's Disease Research Center, and a member of the Hope Center for Neurological Disorders.

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 the amyloid-β (Aβ) peptide in AD pathogenesis. Changes in Aβ conformation from soluble, relatively unstructured forms to both soluble and insoluble forms with high β-sheet content appears to be a key event in AD and cerebral amyloid angiopathy (CAA). We are particularly interested in understanding Aβ metabolism within different compartments in the CNS as well as in the periphery. We believe that a better understanding of Aβ metabolism in both the CNS and periphery will lead to a much better understanding of factors that predispose to AD as well as better diagnostics and treatments. Some of the factors we are studying that control Aβ metabolism include the role of endogenous and exogenous Aβ binding molecules in regulating Aβ metabolism. An important genetic risk factor for Alzheimer's disease and poor recovery after brain injury is the apolipoprotein E (apoE) gene. The E4 allele of apoE is associated with increased risk and the E2 allele with decreased risk for AD. Utilziing mice expressing different human apoE isoforms and a mouse model with Alzheimer's disease pathology, we have demonstrated that interactions between apoE, apoE receptors, and Aβ influence the level, conformation, and toxicity of apoE and Aβ in vivo. Aggregation of Aβ in the brain of the mouse models occurs in an isoform-specific pattern (E4>E3>E2). These effects are likely to be relevant to the mechanism(s) underlying why apoE contributes to AD pathogenesis. We are exploring the effects of modifying apoE lipidation via the protein ABCA1. We have recently found that decreased ABCA1 increases amyloid deposition and increased ABCA1 markedly suppresses amyloid deposition. We are interested in understanding the mechanisms underlying these effects. In addition to experiments with endogenous Aβ -binding molecules, we have also been examining the effects of certain exogenously administered anti-Aβ antibodies and secretase inhibitors in an animal model of AD to further understand the effects of these reagents on Aβ metabolism as well as their potential use in the diagnosis and treatment of AD. Several other recent and active areas of interest include 1) the role of the blood-brain-barrier and P-glycoprotein in Aβ transport from CNS to blood; 2) the role of synaptic activity in dynamically regulating Aβ in the brain; 4) determining biomarkers for antecedent Alzheimer's disease using techniques such as proteomics; and 5) determining better ways to study Aβ synthesis and clearance in both animals and humans.

Hypoxic-ischemic (H-I) injury to the neonatal brain is a frequent cause of encephalopathy, seizures, and motor impairment (cerebral palsy). Our lab is interested in further understanding mechanisms of brain injury following neonatal H-I as well as developing potential treatments to prevent or limit brain injury. We have found that both rapid, excitotoxic/necrotic death as well as apoptotic-like death are prominent in a rodent model of neonatal H-I. However, apoptotic-like death is much more prominent and delayed in the developing as compared to the adult brain following H-I. We have found that some treatments are particularly protective against H-I induced injury in neonatal animals and are in the process of exploring the cellular and molecular pathways that underlie these effects.

Selected Publications from 2000 to Present:

Han BH, D'Costa A, Back SA, Parsadanian M, Patel S, Shah AR, Gidday JM, Srinivasan A, Deshmukh M, Holtzman DM. BDNF blocks caspase-3 activation in neonatal hypoxia-ischemia. Neurobiology of Disease 2000;7:38-53.

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 2000;97:2892-2897.

Holtzman DM, Fagan AM, Mackey B, Tenkova T, Sartorius L, Paul SM, Bales K, Ashe KH, Irizzary MC, Hyman BT. (2000) ApoE facilitates neuritic and cerebrovascular plaque formation in the APPsw mouse model of Alzheimer's disease. Ann Neurol 47:739-747.

Fagan AM, Younkin LH, Morris JC, Cole TG, Younkin SG, Holtzman DM. (2000) Differences in Ab 40/42 ratio associated with CSF lipoproteins as a function of apoE genotype. Ann. Neurol. 48:201-210.

Han BH, DeMattos RB, Dugan LL, Kim-Han JS, Brendza R, Fryer JD, Kierson M, Cirrito J, Quick K, Harmony JAK, Aronow BJ, Holtzman DM. (2001) Clusterin contributes to caspase-3 independent brain injury following neonatal hypoxia-ischemia. Nature Med. 7:338-343.

DeMattos RB, Bales KR, Cummins DJ, Dodart J-C, Paul SM, Holtzman DM. (2001) Peripheral anti-Ab antibody alters CNS and plasma Ab clearance and decreases brain Ab burden in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 98: 8850-8855:10.1073/pnas.151261398.

DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM. (2002) Brain to plasma amyloid-b efflux: A measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science 295:2264-2267.

DeMattos RB, Bales KR, Kierson ME, O'Dell MA, Foss EM, Paul SM, Holtzman DM. (2002) Plaque associated disruption of CSF and plasma Ab equilibrium in a mouse model of Alzheimer's disease. J. Neurochem. 81:229-236.

Fagan AM, Watson M, Parsadanian M, Bales KR, Paul SM, Holtzman DM. (2002) Human and murine apoE markedly influence Ab metabolism before and after plaque formation in a mouse model of Alzheimer's disease. Neurobiol. Dis. 9:305-318.

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 Ab burden in Alzheimer's disease model. Nature Neurosci. 5:452-457.

Han BH, Xu D, Choi J, Han Y, Xanthoudakis S, Roy S, Tam J, Vaillancourt J, Colucci J, Siman R, Giroux A, Robertson GS, Zamboni R, Nicholson DW,

Holtzman DM. (2002) Selective, reversible caspase-3 inhibitor is neuroprotective and reveals distinct pathways of cell death following neonatal hypoxic-ischemic brain injury. J. Biol. Chem. 277:30128-30136.

Arvin KL, Han BH, Du Y, Lin S, Paul SM, Holtzman DM. (2002) Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Ann. Neurol. 52:54-61.

DeMattos RB, O'Dell MA, Parsadanian M, Taylor JW, Harmony JAK, Bales KR, Paul SM, Aronow BJ, Holtzman DM. (2002) Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 99:10843-10848. (10.1073/pnas.162228299)

Hartman RE, Laurer H, Longhi L, Bales KR, Paul SM, McIntosh TK, Holtzman DM. (2002) APOE4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer's disease. J. Neurosci. 22:10083-10087.

Brendza RP, O'Brien C, Simmons K, McKeel DW, Bales KR, Paul SM, Olney JW, Sanes JR,, Holtzman DM. (2003) PDAPP;YFP double transgenic mice: A tool to study amyloid-b associated changes in axonal, dendritic, and synaptic structure. J. Comp. Neurol. 456:375-383.

Fryer JD, Taylor JW, DeMattos RB, Bales KR, Paul SM, Parsadanian M, Holtzman DM (2003) Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in APP transgenic mice. Journal of Neuroscience 23: 7889-7896.

Cirrito JR, May PC, O'Dell MA, Taylor JW, Parsadanian M, Cramer JW, Audia JE, Nissen JS, Bales KR, Paul SM, DeMattos RB, Holtzman DM. (2003) In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-b metabolism and half-life. Journal of Neuroscience 23:8844-8853.

DeMattos R, Cirrito J, O'Dell M, Taylor J, Harmony J, Aronow B, Bales K, Paul S, Holtzman DM. (2004) ApoE and clusterin cooperative suppress Ab levels and deposition: Evidence that ApoE regulates extracellular Ab metabolism in vivo. Neuron 41:193-202.

Wahrle, SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, Kowalewski T and Holtzman, DM (2004) ABCA1 is required for normal CNS apoE levels and for lipidation of astrocyte-secreted apoE. Journal of Biological Chemistry 279(39):40987-20993.

Brendza RP, Bacskai BJ, Cirrito JR, Simmons KA, Skoch JM, Klunk WE, Mathis CA, Bales KR, Paul SM, Hyman BT, Holtzman DM. Anti- Ab antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. J Clin Invest. 2005; 115: 428-433.

Morikawa M, Fryer JD, Sullivan PM, Christopher EA, Wahrle SE, DeMattos RB, O'Dell MA, Fagan AM, Lashuel HA, Walz T, Asai K, Holtzman DM. (2005) Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-b. Neurobiology of Disease 19:66-76.

Fryer JD, Simmons K, Parsadanian M, Bales KR, Paul SM, Sullivan PM, Holtzman DM. (2005) Human apolipoprotein E4 alters the amyloid-b 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. Journal of Neuroscience 25:2803-2810.

Loren DJ, Seeram NP, Schulman RN, Holtzman DM. (2005) Maternal Dietary Supplementation with Pomegranate Juice Is Neuroprotective in an Animal Model of Neonatal Hypoxic-Ischemic Brain Injury. Pediatric Research 57:858-864.

Hartman RE, Izumi Y, Bales KR, Paul SM, Wozniak DF, Holtzman DM. (2005)
Treatment with an amyloid-b antibody ameliorates plaque load, learning deficits, and hippocampal long-term potentiation in a mouse model of Alzheimer's disease. Journal of Neuroscience 25: 6213 - 6220.

Hu Y, Townsend RR, Fagan AM, Holtzman DM. (2005) Comparative proteomic analysis of intra- and inter-individual variation in human cerebrospinal fluid. Molecular and Cellular Proteomics 4(12):2000-9.

Wahrle SE, Jiang H, Parsadanian M, Hartman RE, Bales KR, Paul SM, Holtzman DM (2005) Deletion of Abca1 increases Ab deposition in the PDAPP transgenic mouse model of Alzheimer's disease Journal of Biological Chemistry 280(52):43236-43242.

Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Jiang H, Prior JL, Sagare A, Bales KR, Paul SM, Zlokovic BV, Piwnica-Worms D, Holtzman DM. (2005) P-glycoprotein deficiency at the blood-brain barrier increases amyloid-b deposition in an Alzheimer's disease mouse model. J. Clin. Invest. 115: 3285 - 3290.

Cirrito JR, Yamada KA, Finn MB, Sloviter RS, 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.

Brody D, Holtzman DM. (2006) Morris water maze search strategy analysis in PDAPP mice before and after experimental traumatic brain injury.Exp Neurol. 197(2):330-40.

West T, Atzeva M, Holtzman DM (2006) Caspase-3 deficiency during development increases vulnerability to hypoxic-ischemic injury through caspase-3-independent pathways. Neurobiol Dis. 22(3):523-37.

Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, LaRossa GN, Spinner ML, Klunk WE, Mathis CA, DeKosky ST, Morris JC, Holtzman DM. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol. 2006 Mar;59(3):512-9. PMID: 16372280 [PubMed - indexed for MEDLINE]

Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med. 2006 Jul;12(7):856-61. Epub 2006 Jun 25.

Hartman RE, Shah A, Fagan AM, Schwetye KE, Parsadanian M, Schulman RN, Finn MB, Holtzman DM. Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer's disease. Neurobiol Dis. 2006 Dec;24(3):506-15. Epub 2006 Sep 28.

Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007 Mar;64(3):343-9. Epub 2007 Jan 8.

Bateman RJ, Wen G, Morris JC, Holtzman DM. Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker.
Neurology. 2007 Feb 27;68(9):666-9. PMID: 17325273 [PubMed - indexed for MEDLINE]

Wahrle SE, Shah AR, Fagan AM, Smemo S, Kauwe JS, Grupe A, Hinrichs A, Mayo K, Jiang H, Thal LJ, Goate AM, Holtzman DM. Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1 polymorphisms. Mol Neurodegener. 2007 Apr 12;2:7. PMID: 17430597 [PubMed - in process]

West T, Atzeva M, Holtzman DM. Pomegranate polyphenols and resveratrol protect the neonatal brain against hypoxic-ischemic injury.
Dev Neurosci. 2007;29(4-5):363-72.

Kang JE, Cirrito JR, Dong H, Csernansky JG, Holtzman DM. Acute stress increases interstitial fluid amyloid-beta via corticotropin-releasing factor and neuronal activity. Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10673-8. Epub 2007 Jun 5.

Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM, Holtzman DM. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest. 2008 Jan 17; [Epub ahead of print], 118(2):671-682.

Cirrito JR, Kang J-E, LeeJ, Stewart FR,­­Verges D, Silverio LM BuG, MennerickS, Holtzman DM. Endocytosis is required for synaptic activity-dependent release of amyloid-b in vivo. Neuron 2008 58:42-51.