Contact

Department

Cellular and Integrative Physiology

Veronica Galvan, Ph.D.

Associate Professor

Education

M.S., Centro de Altos Estudios en Ciencias Exactas University, Buenos Aires, 1994
Ph.D., University of Chicago, 1999

Research

Visit our lab website for more details at

www.galvanlab.org

Alzheimer’s disease (AD) is an incapacitating age-related neurodegenerative disorder characterized by memory loss and progressive deterioration of cognitive function. AD and AD-related dementia accounts for more than 60% of all dementia cases. Current treatment options for AD are limited, and only temporarily palliative.  Because of its high prevalence and the continuing increase of the aged population, AD is a major health problem with serious negative consequences for affected individuals and their families, as well as local and worldwide economies.

Our research is focused on the identification of molecular and biochemical alterations that cause AD.  By understanding how AD is triggered and how it develops, we can devise ways to slow or prevent the disease. We use genetic manipulations in mouse models, behavioral, immunohistochemical and biochemical approaches, in vivo brain optical and functional imaging, in vivo brain blood flow measures, and cellular and molecular biology tools to understand the initiating molecular events in AD, determine the effects of potential drug candidate molecules, and define the mechanisms involved.

Amyloid-ß regulation. Late stage AD is characterized by brain lesions that include amyloid plaques enriched in amyloid-beta (Aß) and neurofibrillary tangles containing misfolded forms of the microtubule-binding protein tau. Understanding the mechanisms by which Aß and tau are dysregulated and become pathogenic is needed to formulate strategies to prevent or treat AD.  Using surrogate models of AD, we have identified a key role of the mammalian target of rapamycin (TOR), a major regulator of metabolism and organismal aging, in the control of brain Aß levels through the modulation of autophagy.

Reduced cerebral blood flow and blood-brain barrier breakdown in AD:The earliest stages of AD are marked by decreased cerebral blood flow and blood-brain barrier (BBB) breakdown.  Understanding the causes for diminished cerebral blood flow and BBB collapse in AD will allow us to devise methods to slow or block progression of the disease at its earliest stage. We recently identified TOR-dependent mechanisms that drive the decrease in brain blood flow in AD models through the inhibition of endothelial nitric oxide synthase (eNOS) and the collapse of BBB through downregulation of the key tight junction scaffold protein junctional adhesion protein A (JAM-A).  Our studies show that preservation of endothelium-dependent vasodilation is required for the restoration of cerebral blood flow in models of AD, and that the resulting increase in brain circulation enables the continuous elimination of Aß from brain.  mTOR is thus involved in the control of net Aß levels through autophagy in neurons, and in the regulation of clearance of Aß from brain through the cerebral vasculature. Drugs that attenuate mTOR thus establish a feedforward loop that reduces net Aß levels in brain by simultaneously reducing its production and increasing its elimination from brain.

Microvascular tau in AD and other tauopathies:  We recently showed that prefilamentous aggregates of hyper-phosphorylated tau (tau oligomers) accumulate in brain microvessels of AD and of progressive supranuclear palsy (PSP) patients, suggesting that, like Aß, extracellular tau may propagate to non-neuronal cell types and thus contribute to brain microvascular dysfunction in AD and other neurodegenerations associated with tauopathy.  We are currently exploring the co-occurrence of misfolded tau and Aß in cerebrovasculature of AD and PSP, and the propagation of misfolded tau oligomers to non-neuronal cell types in AD brain.

So far, our research has led us to discover a key role of TOR in the initiation of neuronal and brain vascular dysfunction in AD through pathways involving Aß and tau.  Because TOR controls key aspects of metabolism in most cell types we hypothesize that TOR may be involved in several cell-specific complex disease mechanisms driving neurodegeneration in AD. Thus, to define the role of TOR in AD, we study mechanisms by which pathways centered on TOR but mediating distinct processes in different brain compartments such as neurons and brain vascular cells synergize to precipitate loss of function.  Based on our findings, we are currently engaged in safety studies of rapamycin, and in drug screening/drug discovery efforts in a search for (a) compounds that regulate the activity of the TOR pathway and (b) compounds that regulate JAM-A levels, that may be used to slow or treat AD and potentially other dementias.

Lab Members

Graduate Student
 Nicholas DeRosa
Research Associate – Senior
 Stephen Hernandez
Student Associate
 Stacy Hussong, Ph.D.
Instructor – Research
Graduate Student
Postdoctoral Fellow

News

Dr. Candice Van Skike’s recent paper in the American Journal of Physiology Heart Circ Physiol was selected as an APSselect “Best Article”
Van Skike CE, Jahrling JB, Olson AB, Sayre NL, Hussong SA, Ungvari ZI, Lechleiter JD, Galvan V. (2018) Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer’s disease and vascular cognitive impairment. Am J Physiol Heart Circ Physiol. 2018 Apr 1; 314:H693-H703. PMID: 29351469      Article selected as American Physiological Society’s APSselect ‘Best Articles

Dr. Stacy Hussong received a American Aging Association Junior Faculty Award (that included selection for an oral presentation and a Travel Award) at the recent 2018 American Aging Association Annual Meeting in Philadelphia

Dr. Candice Van Skike received an “American Aging Association Achievement Award” for 1st Place Oral Postdoctoral Presentation at the National American Aging Association Trainee Data Blitz at the same meeting

Angie Olson received an American Aging Association Graduate Student Travel Award (for the same meeting)

Stephen Hernandez received an  award for aSuperior Poster Presentation by a pre-doctoral student” (same meeting)

Publications

Cerebral Microvascular Accumulation of Tau Oligomers in Alzheimer’s Disease and Related Tauopathies.
Castillo-Carranza DL, Nilson AN, Van Skike CE, Jahrling JB, Patel K, Garach P, Gerson JE, Sengupta U, Abisambra J, Nelson P, Troncoso J, Ungvari Z, Galvan V, Kayed R.
Aging Dis. 2017 May 2;8(3):257-266. doi: 10.14336/AD.2017.0112. eCollection 2017 May.
PMID: 28580182

mTOR drives cerebral blood flow and memory deficits in LDLR-/- mice modeling atherosclerosis and vascular cognitive impairment.
Jahrling JB, Lin AL, DeRosa N, Hussong SA, Van Skike CE, Girotti M, Javors M, Zhao Q, Maslin LA, Asmis R, Galvan V.
J Cereb Blood Flow Metab. 2017 Jan 1:271678X17705973. doi: 10.1177/0271678X17705973. [Epub ahead of print]
PMID: 28511572

Vascular mTOR-dependent mechanisms linking the control of aging to Alzheimer’s disease.
Galvan V, Hart MJ.
Biochim Biophys Acta. 2016 May;1862(5):992-1007. doi: 10.1016/j.bbadis.2015.11.010. Epub 2015 Nov 27.
PMID: 26639036

Lin A, Halloran JJ, Burbank RR, Korde S, Zheng W, Hussong SA, Podlutskaya N, Strong R, Richardson A, Hart MJ, Fox PT, Lechleiter J, Galvan V (2013). Chronic rapamycin restores brain vascular density and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer’s disease. J Cereb Blood Flow Metab. Jun 26. PMID: 23801246.

Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer’s disease.
Lin AL, Zheng W, Halloran JJ, Burbank RR, Hussong SA, Hart MJ, Javors M, Shih YY, Muir E, Solano Fonseca R, Strong R, Richardson AG, Lechleiter JD, Fox PT, Galvan V.
J Cereb Blood Flow Metab. 2013 Sep;33(9):1412-21. doi: 10.1038/jcbfm.2013.82. Epub 2013 Jun 26.
PMID: 23801246

Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice.
Halloran J, Hussong SA, Burbank R, Podlutskaya N, Fischer KE, Sloane LB, Austad SN, Strong R, Richardson A, Hart MJ, Galvan V.
Neuroscience. 2012 Oct 25;223:102-13. doi: 10.1016/j.neuroscience.2012.06.054. Epub 2012 Jun 28. Erratum in: Neuroscience. 2015 Oct 15;306():151.
PMID: 22750207

Over-expression of heat shock factor 1 phenocopies the effect of chronic inhibition of TOR by rapamycin and is sufficient to ameliorate Alzheimer’s-like deficits in mice modeling the disease.
Pierce A, Podlutskaya N, Halloran JJ, Hussong SA, Lin PY, Burbank R, Hart MJ, Galvan V.
J Neurochem. 2013 Mar;124(6):880-93. doi: 10.1111/jnc.12080. Epub 2012 Dec 26.
PMID: 23121022

 Halloran JJ, Hussong S, Podlutskaya N, Burbank R, Austad S, Hart MJ, Fischer K and Galvan V. (2012) Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neurosci. June 28. PMID: 22750207.

Pierce A, Podlutskaya NP, Halloran JJ and Galvan V (2012) Over-expression of heat shock factor 1 phenocopies the effect of chronic inhibition of TOR by rapamycin and is sufficient to ameliorate Alzheimer’s-like deficits in mice modeling the disease. J Neurochem. December 26. DOI: 10.1111/jnc.12080. View Editorial Highlight.

Lin A, Halloran JJ, Burbank RR, Korde S, Zheng W, Hussong S, Podlutskaya N, Strong R, Richardson A, Fox PT, Lechleiter J, Hart MJ, Galvan V (2012) Chronic rapamycin restores brain vascular integrity through eNOS activation and improves memory in mice modeling Alzheimer’s diseaseJ Cereb Blood Flow and Metab. In review.

Zhang J, Rao R, Spilman P, Mangada J, Xie L, Vitelli C, Gorostiza OF, Madden DT, Zeng X, Jin K, Hart MJ, Bredesen DE and Galvan V (2011) Endogenously EGFP-Labeled Mouse Embryonic Stem Cells. Aging and Dis. 2:18-29.

Hart MJ, Sharma MK, Liu M, Cuny GD, Glicksman MA and Galvan V (2011) A highly-sensitive high-throughput screen targeting caspase 8-mediated cleavage of the amyloid precursor protein. Analytical Biochemistry. 421:467-76.

Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease.
Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V.
PLoS One. 2010 Apr 1;5(4):e9979. doi: 10.1371/journal.pone.0009979. Erratum in: PLoS One. 2011;6(11). doi:10.1371/annotation/05c1b976-7eab-4154-808d-0526e604b8eb.
PMID: 20376313

 Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Richardson A, Strong R and Galvan V (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS One. 5:e9979.

Calheiros F, Galvan V, Corset V, Llambi F, Bredesen DE, and Mehlen P. (2009) Netrin-1 acts as an amyloid precursor protein ligand and suppresses amyloid-ß production. Cell Death Differ. 16:655-63.

Jin K, Mao X, Xie L, Galvan V, Lai B, Wang Y, Gorostiza O, Wang X, Greenberg D. (2009) Transplantation of human neural precursor cells in matrigel scaffolding improves outcome from focal cerebral ischemia after delayed postischemic treatment in rats. J Cereb Blood Flow and Metab. Oct 14. PMID: 19826433.

Vogt DL, Thomas D, Liang M, Galvan V, Bredesen DE, Lamb BT and Pimplikar SW. (2009) Abnormal neuronal networks and seizure susceptibility in transgenic mice overexpressing the APP intracellular domain. Neurobiol Aging. Oct 12. PMID: 19828212.

Zhang J, Gorostiza O, Tang H, Bredesen DE, Galvan V (2009) Reversal of learning deficits in hAPP transgenic mice carrying a mutation at Asp664: A role for early experience. Beh Brain Res 206:202-07.

Nguyen T, Galvan V, Zhang J, Bredesen DE. (2008) p21-activated kinase signaling requires C-terminal cleavage of APP at Asp664. J Neurochem 104: 1065-80.

Galvan V, Zhang J, Gorostiza O, Tang H, Huang W, Banwait S, Ataie M, Bredesen DE. (2008) Long-term prevention of Alzheimer’s disease-like behavioral deficits in PDAPP mice carrying a mutation in Asp664. Beh Brain Res. 191:246-55.

Tang H, Wang Y, Xie L, Mao X, Won SJ, Galvan V, Jin K. (2007) Effect of neural precursor proliferation level on neurogenesis in rat brain during aging and after focal ischemia. Neurobiol Aging 104:1065.

Galvan V, Banwait S, Spilman PR, Gorostiza OF, Peel A, Sidhu G, Tang, H, Ichijo H and Bredesen DE. (2007) Interaction of ASK1 and the beta-amyloid precursor protein in a stress-signaling complex. Neurobiol dis. 28:65-75.

Saganich MJ, Schroeder BE, Galvan V, Bredesen DE, Koo EH, Heinemann SF. (2006) Deficits in synaptic transmission and learning in APP transgenic mice require C-terminal cleavage of APP. J Neurosc. 26:13428.

Wang Y, Galvan V, Gorostiza O, Ataie M, Jin K and Greenberg D. (2006) Vascular endothelial growth factor improves recovery of sensorimotor and cognitive deficits after focal cerebral ischemia in the rat. Brain Res 1115:186-93.

Galvan V, Gorostiza OF, Banwait S, Ataie M, Logvinova AV, Sitaraman S, Carlson E, Sagi SA, Chevallier N, Jin K, Greenberg DA, Bredesen DE. (2006) Reversal of Alzheimer’s-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc Natll Acad Sci USA. 103:7130-35.

Semenov I, Wang B, Herlihy JT, Brenner R. BK channel beta1-subunit regulation of calcium handling and constriction in tracheal smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2006 Oct;291(4):L802-10.

Jin K, Galvan V, Xie L, Mao XO, Gorostiza OF, Bredesen DE, Greenberg D. (2004) Enhanced neurogenesis in Alzheimer’s disease transgenic (PDGF-APPSw,Ind) mice. Proc Natl Acad Sci U S A. 101: 13363-67.

Galvan V, Kurakin A. and Bredesen DE. (2003) Interaction of checkpoint kinase 1 and the X-linked inhibitor of apoptosis during mitosis. FEBS Letters 558: 57-62.

Galvan V, Logvinova A, Sperandio S, Ichijo H and Bredesen DE. (2003) Type 1 Insulin-like growth factor receptor (IGF-IR)signaling inhibits apoptosis signal-regulating kinase 1 (ASK1). J Biol Chem. 278:13325.

Ikeno Y, Hubbard GB, Lee S, Yu BP, Herlihy JT. The influence of long-term aloe ingestion on age-related disease in male Fischer 344 rats. Phytother. Res. Phytother Res. 16(8):712-8, Dec 2002. 

Klebanov S, Herlihy JT, Freeman GL. Assessing effects of long-term food restriction on myocardial energetics in the isolated heart preparation. Mech Ageing Dev;123(10):1375-88, Jul 2002.

Ikeno Y, Hubbard GB, Lee S, Yu BP, Herlihy JT. The influence of long-term Aloe vera ingestion on age-related disease in male Fischer 344 rats. Phytother Res. 2002 Dec;16(8):712-8.

Galvan V, Chen S, Lu D, Koo EH and Bredesen DE. (2002) Caspase cleavage of members of the amyloid precursor family of proteins. J Neurochem. 82: 283-4.

Kim JW, Back BS, Kim YK, Herlihy JT, Ikeno Y, Yu BP, Chung HY. Gene expression of cyclooxygenase in the aging heartJ. Gerontol. 56: B350-B355, 2001. 

Kim YK, Herlihy JT. Mechanism of sodium nitroprusside (SNP) action on ischemia-reperfusion (IR). FASEB J. 15: A430, 2001 

Kim YK, Herlihy JT. Protective effects of sodium nitroprusside (SNP) on ischemia-reperfusion (IR) injury. FASEB J. 14: A684, 2000

Lee J, Yu BP, Herlihy JT. Modulation of cardiac mitochondrial membrane fluidity by age and calorie intake. Free Rad. Biol. Med. 26: 260-265, 1999.

Kelly GR, Herlihy JT. Food restriction alters the age-related decline in cardiac beta-adrenergic responsiveness. Mech. Ageing and Dev. 103: 1-12, 1998 

Galvan V and Roizman B. (1998) Herpes simplex virus 1 induces and blocks apoptosis at multiple steps during infection and protects cells from exogenous inducers in a cell-type-dependent manner. Proc. Natl. Acad. Sci. USA 95:3931-36.

 

Klebanov S  Herlihy, JT. Effect of life-long food restriction on cardiac myosin composition. J. Gerontol. 52A:B184-B189, 1997. 

Klebanov S, Herlihy JT Freeman GL. Effect of long-term food restriction on cardiac mechanics. Am. J. Physiol. 273:H2333-H2342, 1997.

Kim JD, Yu BP, McCarter JM, Lee SY, Herlihy JT. Exercise and diet modulate cardiac lipid peroxidation and antioxidant defenses. Free Radicals in Biol. & Med. 20:83-88, 1996.

 

Lin A, Pulliam D, Sathyaseelan D, Halloran JJ, Burbank RR, Hussong SA, Bresnen A, Soundararajan A, Muir E, Duong TQ, Viscomi C, Zeviani M, Richardson AG, Van Remmen H,  Fox PT, Galvan V(2013) Decreased Mitochondrial Function With Surf1 Deficiency Enhances Brain Metabolism and Cognition in Mice. J Cereb Blood Flow Metab. Jul 10. PMID: 23838831.