Shannon L. Macauley-Rambach, PhD

Assistant Professor of Neurology

Phone314-362-5503

Emailshannon.macauley@wustl.edu

Education

  • Postdoctoral Fellow: Washington University, St. Louis, MO (2015)
  • Doctor of Philosophy: Washington University, St. Louis, MO (2009)
  • Bachelor of Arts: Middlebury College, Middlebury, VT (1999)

Recognition

  • NIH Mentored Research Scientist Career Development Award (K01), NIA (2016-Present)
  • Charleston Conference on Alzheimer’s Disease (CCAD) New Vision Award Winner, Charleston SC (2015)
  • Hope Center Award for Translational Neuroscience, Washington University, St Louis MO (2014)
  • Hope Center Award for Translational Neuroscience, Washington University, St Louis MO (2011)
  • Alfred Rider Memorial Research Award, Batten Disease Support & Research Association (2009)
  • Vice President’s Award, Genzyme Corporation, Framingham, MA (2003)

Research Interests

The focus of my research is to understand diseases of the central nervous system (CNS) and how secondary mechanisms, such altered CNS metabolism, impact neuronal health and function.  Ultimately, the goal is to leverage these findings as therapeutic targets for treating neurodegenerative disorders.  My work is focused in two main areas: 1) the interplay between Alzheimer’s disease (AD) and type-2-diabetes (T2D) and 2) the understanding and treatment of lysosomal storage diseases (LSDs).

Patients with T2D have an increased risk for AD.  Hyperglycemia, hyperinsulinemia, and insulin resistance have all been linked to dementia and dementia of an Alzheimer’s type. Therefore, I explore how key features of T2D, such as alterations in glucose and insulin, affect the hallmarks of AD pathology, including amyloid-β (Aβ) and tau production, aggregation, and accumulation.  Hyperglycemia alone can affect human cognitive function, default mode network processing, and spontaneous brain activity, suggesting that disrupted glucose homeostasis affects neurodegenerative processes associated with cognitive dysfunction and AD. Our research demonstrates that hyperglycemia modulates extracellular concentrations of amyloid-β (Aβ) in an activity-dependent manner through KATP channel activity.  Using methods that couple in vivo microdialysis and glucose clamps in animal models of AD, current work focuses on how hyperglycemia affects neuronal activity, synaptic plasticity and network connectivity in the context of healthy aging and AD pathology.  We also continue to explore the role of the KATP channel activity in AD, both in terms of disease pathogenesis and therapeutic intervention. In concert, we are investigating how peripheral or CNS-directed hyperinsulinemia affects insulin signaling and Aβ levels within the brain in order to further understand the complex relationship between T2D and AD. Given my interest in CNS metabolism, we are currently investigating why regions prone to Aβ deposition are more metabolically active, resulting in a unique metabolic signature compared to other regions in the brain.  Not only has this been observed in human patients with AD, it is seen in mouse models of cerebral amyloidosis.  We recently found that alterations in key glycolytic enzymes involved in aerobic glycolysis are altered as a function of age and Aβ, impacting learning and memory differentially.

In addition to my interests in T2D and AD, I study mechanisms of neurometabolism, neurodegeneration, and neuroinflammation in lysosomal storage diseases (LSD) and how targeting different aspects of pathology with combination therapies enhances efficacy.  Our findings not only characterized the temporal-spatial spread of CNS disease and functional deficits in mouse models of Niemann-Pick Type A, infantile neuronal ceroid lipofuscinosis, Pompe disease, Krabbe disease, and late-infantile neuronal ceroid lipofuscinosis, but also identified secondary disease mechanisms associated with neurodegeneration that need to be addressed in treatment strategies for these disorders.

Publications

  • Shyng C, Macauley SL, Dearborn JT, Sands MS. Widespread Expression of a Membrane-Tethered Version of the Soluble Lysosomal Enzyme Palmitoyl Protein Thioesterase-1. JIMD reports. 2017; PubMed [journal] PMID: 28213849
  • Stanley M, Macauley SL, Caesar EE, Koscal LJ, Moritz W, Robinson GO, Roh J,Keyser J, Jiang H, Holtzman DM. The Effects of Peripheral and Central High Insulin on Brain Insulin Signaling and Amyloid-β in Young and Old APP/PS1 Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2016; 36(46):11704-11715. PubMed [journal] PMID: 27852778, PMCID:PMC5125227
  • Stanley M, Macauley SL, Holtzman DM. Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence? The Journal of experimental medicine. 2016; 213(8):1375-85. PubMed [journal] PMID: 27432942, PMCID: PMC4986537
  • Macauley SL. Combination Therapies for Lysosomal Storage Diseases: A Complex Answer to a Simple Problem. Pediatric endocrinology reviews : PER. 2016; 13 Suppl1:639-48. PubMed [journal] PMID: 27491211
  • Harris RA, Tindale L, Lone A, Singh O, Macauley SL, Stanley M, Holtzman DM, Bartha R, Cumming RC. Aerobic Glycolysis in the Frontal Cortex Correlates with Memory Performance in Wild-Type Mice But Not the APP/PS1 Mouse Model of Cerebral The Journal of neuroscience : the official journal of the Societyfor Neuroscience. 2016; 36(6):1871-8. PubMed [journal] PMID: 26865611, PMCID: PMC4748073
  • Macauley SL, Stanley M, Caesar EE, Yamada SA, Raichle ME, Perez R, Mahan TE, Sutphen CL, Holtzman DM. Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo. The Journal of clinical investigation. 2015; 125(6):2463-7. PubMed [journal] PMID: 25938784, PMCID:PMC4497756
  • Macauley SL, Holtzman DM. Recent Advances from the Bench Toward the Bedside in Alzheimer’s Disease. EBioMedicine. 2015; 2(2):94-5. PubMed [journal] PMID: 26137544, PMCID: PMC4484818
  • Macauley SL, Wong AM, Shyng C, Augner DP, Dearborn JT, Pearse Y, Roberts MS, Fowler SC, Cooper JD, Watterson DM, Sands MS. An anti-neuroinflammatory that targets dysregulated glia enhances the efficacy of CNS-directed gene therapy in murine infantile neuronal ceroid lipofuscinosis. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2014; 34(39):13077-82. PubMed [journal] PMID: 25253854, PMCID: PMC4172802
  • Roberts MS, Macauley SL, Wong AM, Yilmas D, Hohm S, Cooper JD, Sands MS. Combination small molecule PPT1 mimetic and CNS-directed gene therapy as a treatment for infantile neuronal ceroid lipofuscinosis. Journal of inheritedmetabolic disease. 2012; 35(5):847-57. NIHMSID: NIHMS609910 PubMed [journal] PMID: 22310926, PMCID: PMC4108163
  • Macauley SL, Roberts MS, Wong AM, McSloy F, Reddy AS, Cooper JD, Sands MS. Synergistic effects of central nervous system-directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis. Annals of neurology. 2012; 71(6):797-804. NIHMSID: NIHMS353711 PubMed [journal] PMID: 22368049, PMCID: PMC3369009
  • Macauley SL, Pekny M, Sands MS. The role of attenuated astrocyte activation in infantile neuronal ceroid lipofuscinosis. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2011; 31(43):15575-85. NIHMSID: NIHMS336360 PubMed [journal] PMID: 22031903, PMCID: PMC3218425
  • Reddy AS, Kim JH, Hawkins-Salsbury JA, Macauley SL, Tracy ET, Vogler CA, Han X, Song SK, Wozniak DF, Fowler SC, Klein RS, Sands MS. Bone marrow transplantation augments the effect of brain- and spinal cord-directed adeno-associated virus 2/5 gene therapy by altering inflammation in the murine model of globoid-cell leukodystrophy. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2011; 31(27):9945-57. NIHMSID: NIHMS309854 PubMed [journal] PMID: 21734286, PMCID: PMC3348856
  • Kielar C, Wishart TM, Palmer A, Dihanich S, Wong AM, Macauley SL, Chan CH, Sands MS, Pearce DA, Cooper JD, Gillingwater TH. Molecular correlates of axonal andsynaptic pathology in mouse models of Batten disease. Human molecular genetics. 2009; 18(21):4066-80. PubMed [journal] PMID: 19640925, PMCID: PMC2758138
  • Macauley SL, Sands MS. Promising CNS-directed enzyme replacement therapy for lysosomal storage diseases. Experimental neurology. 2009; 218(1):5-8. NIHMSID: NIHMS108720 PubMed [journal] PMID: 19361502, PMCID: PMC2701189
  • Macauley SL, Wozniak DF, Kielar C, Tan Y, Cooper JD, Sands MS. Cerebellarpathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouse. Experimental neurology. 2009; 217(1):124-35. NIHMSID: NIHMS95940 PubMed [journal] PMID: 19416667, PMCID: PMC2679857
  • Macauley SL, Sidman RL, Schuchman EH, Taksir T, Stewart GR. Neuropathology of the acid sphingomyelinase knockout mouse model of Niemann-Pick A disease including structure-function studies associated with cerebellar Purkinje cell degeneration. Experimental neurology. 2008; 214(2):181-92. PubMed [journal] PMID: 18778708
  • Kielar C, Maddox L, Bible E, Pontikis CC, Macauley SL, Griffey MA, Wong M, Sands MS, Cooper JD. Successive neuron loss in the thalamus and cortex in a mouse modelof infantile neuronal ceroid lipofuscinosis. Neurobiology of disease. 2007; 25(1):150-62. NIHMSID: NIHMS14439 PubMed [journal] PMID: 17046272, PMCID:PMC1866219
  • Lin D, Donsante A, Macauley S, Levy B, Vogler C, Sands MS. Central nervous system-directed AAV2/5-mediated gene therapy synergizes with bone marrow transplantation in the murine model of globoid-cell leukodystrophy. Molecular therapy : the journal of the American Society of Gene Therapy. 2007; 15(1):44-52. PubMed [journal] PMID: 17164774
  • Griffey M, Macauley SL, Ogilvie JM, Sands MS. AAV2-mediated ocular gene therapy for infantile neuronal ceroid lipofuscinosis. Molecular therapy : the journal of the American Society of Gene Therapy. 2005; 12(3):413-21. PubMed [journal] PMID: 15979943
  • Passini MA, Macauley SL, Huff MR, Taksir TV, Bu J, Wu IH, Piepenhagen PA, Dodge JC, Shihabuddin LS, O’Riordan CR, Schuchman EH, Stewart GR. AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease. Molecular therapy : the journal of the American Society of Gene Therapy. 2005; 11(5):754-62. PubMed [journal] PMID: 15851014
  • Shihabuddin LS, Numan S, Huff MR, Dodge JC, Clarke J, Macauley SL, Yang W, Taksir TV, Parsons G, Passini MA, Gage FH, Stewart GR. Intracerebral transplantation of adult mouse neural progenitor cells into the Niemann-Pick-A mouse leads to amarked decrease in lysosomal storage pathology. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004; 24(47):10642-51. PubMed [journal] PMID: 15564580
  • Sleat DE, Wiseman JA, El-Banna M, Kim KH, Mao Q, Price S, Macauley SL, Sidman RL, Shen MM, Zhao Q, Passini MA, Davidson BL, Stewart GR, Lobel P. A mouse model ofclassical late-infantile neuronal ceroid lipofuscinosis based on targeted disruption of the CLN2 gene results in a loss of tripeptidyl-peptidase I activity and progressive neurodegeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004; 24(41):9117-26. PubMed [journal] PMID: 15483130
  • Macauley SL, Horsch AD, Oterdoom M, Zheng MH, Stewart GR. The effects of transforming growth factor-beta2 on dopaminergic graft survival. Cell transplantation. 2004; 13(3):245-52. PubMed [journal] PMID: 15191162