Research Interests - Gregory J. Brewer                    October 8, 2013

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We work at the last frontier of biology, the brain.  Our research is directed in two NIH-supported areas: 1) Determine the coding of memory in engineered live neuronal networks reconstructed from the hippocampus 2) epigenetic and redox control of neuron metabolism, aging and Alzheimer disease (AD).  We hypothesize that aging is the last stage of development controlled by epigenetics. 

 

Relevant publications, grouped by research area (last 10 years + a few landmark citations, in numerical order of publication and selectively annotated)

 

Neuronal Networks (reassembling engineered connections of live neurons)

 

29.      Corey, J.M., Wheeler, B.C., and Brewer, G.J. 1996.  Micrometer resolution silane-based patterning of hippocampal neurons: critical variables in photoresist and laser ablation processes for substrate fabrication. IEEE Proc. 43:944-955.PM:9214810 (One of the first demonstrations that neuron growth could be restricted to arbitrary patterns on a substrate and that neuronal somata migrate to the nodes).

36.      Branch D.W., Corey J.M., Weyhenmeyer J.A., Brewer, G.J. and Wheeler, B.C. 1998.  Microstamp patterns of biomolecules for high-resolution neuronal networks.  Med. Biol. Eng. Comput. 36:135-141.PM:9614762          

41.  Wheeler, B C., Corey, J.M., Brewer, G.J. and Branch, D.W.  1999. Microcontact printing for precise control of nerve cell growth in culture.  J. Biomech. Eng. 121:73-78.PM:10080092

48.      Branch, D.W., Wheeler, B.C., Brewer, G.J. and Leckband, D.E.  2000. Long-term maintenance of patterns of hippocampal pyramidal cells on substrates of polyethylene glycol and microstamped polylysine. IEEE Trans.  Biomed. Eng. 47:290-300.PM:10743770

54.      Branch, D.W., Wheeler, B.C., Brewer, G.J. and Leckband,D.E.  2001. Long-term stability of grafted polyethylene glycol surfaces for use with microstamped substrates in neuronal cell culture. Biomaterials 22:1035-1047. PM:11352085

57.      Chang, J.C., Wheeler, B.C. and Brewer, G.J.  2001. Microelectrode array recordings of patterned hippocampal neurons for four weeks.  Biomedical Microdevices 2:245-253. (Process improvements for long-term viability).

58.      Chang, J.C., Brewer, G.J. and Wheeler, B.C.  2001.  Modulation of neural network activity by patterning. Biosensors & Bioelec. 16:527-533.PM:11544046

63.      Chang, J.C., Brewer, G.J.,Wheeler, B.C. 2003.  A Modified Microstamping Technique Enhances Polylysine Transfer and Neuronal Cell Patterning. Biomaterials 24: 2863-2870.PM:12742724 (Process improvements to improve reliability).

64.      Nam, Y., Chang, J.C., Wheeler, B.C., Brewer, G.J. 2004. Gold-coated microelectrode array with thiol linked self-assembled monolayers for engineering neuronal circuits.  IEEE Trans. Biomed. Eng. 51:158-165. PM:14723505  (Improved chemical stability of substrate over periods of weeks).

67.      Nam, Y., J. Chang; D. Khatami; G.J. Brewer; B.C. Wheeler, 2004 Patterning to enhance activity of cultured neuronal networks. IEEE Proc-Nanobiotechnol 151:109-115.   PM: 16475852

68.  Khatami,D., Nam,Y., Brewer,G., Wheeler,B. 2004. Effect of bicuculline on the           spontaneous and evoked activity of patterned embryonic hippocampal neurons cultured in vitro.  Conf. Proc. IEEE EMBS 6:4059-4062. PM:17271191

70.      Vogt, A.K., Brewer, G.J., Decker, T., Boecker-Meffert, S., Jacobsen, V., Kreiter, M., Knoll, W., Offenhausser, A. 2005. Independence of synaptic specificity from neuritic guidance. Neuroscience., 134:783-790. PM:16009499 (Identifies proportions of excitatory and inhibitory synapses.)

71.      Vogt,A.K.; Brewer,G.J.; Offenhausser,A. 2005.  Connectivity patterns in neuronal networks of experimentally defined geometry, Tissue Eng, 11:1757-1767.  PM:16411821

Text Box: Largely unidirectional flow of information in the hiipocampus for learning and memory

 

 

 

 

 

 

 

73.      Chang, J.C., Brewer, G.J, Wheeler, B.C. 2006.  Neuronal network structuring induces greater neuronal activity through enhanced astroglial development, J. Neural Eng. 3:217-226. PM: 1692105.

76. Rowe, L, Almasri, M., Lee, K., Fogleman, N., Brewer, G.J., Nam, Y., Wheeler, B.B., Vukasinociv, V., Glezer, A., Frazier, A.B., 2007. Active 3-D Microscaffold System with Fluid Perfusion for Culturing in Vitro Neuronal Networks,  Lab Chip 7:475-482. PM:17389964 (First 3D patterned growth of neurons).

77. Boehler, M.D., Wheeler, B.C., Brewer, G.J. 2007.  Added astroglia promote greater synapse density and higher activity in neuronal networks, Neuron Glia Biology 3:127-140.  PM:18345351.  PMCID: PMC2267743 (Clear role of astroglia to enhance network firing dynamics).

80.      Nam, Y, Brewer, GJ, Wheeler, BC. 2007.  Development of astroglial cells in patterned neuronal cultures, J. Biomaterials Science, Polymer Edition 18:1091-1100. PM:17706000

83.      Vernekar, V. N., Cullen, D.K., Fogleman, N, Choi, Y, Garcia, A.J., Allen, M.G., Brewer, G.J., LaPlaca, M.C. 2008.  Cytocompatibility of SU-8 2000 with primary neuronal cultures, J Biomed Mater Res A 89:138-151. PM:18431778.

Text Box:  Text Box: Red NMDA receptor-tagged  excitatory synapses, green GABA-receptor inhibitory synapses 86. Brewer, G.J., Boehler, MD; Jones, TT, Wheeler, BC. 2008. NbActiv4 medium for neurons increases synaptic densities and network spike rates on multielectrode arrays compared to Neurobasal/B27.  J. Neurosci. Meth. 170:181-187. PM:18308400  PMC2393548 (Designed selective nutrients to enhance synaptogenesis and consequent network dynamics; first improvement to Neurobasal/B27 in 15 years).

 

 

 

88.      Brewer, G. J., Boehler M.D., Pearson, R., DeMaris, A., Wheeler, B.C. 2009. Neuron Network Activity Scales Exponentially with Synapse Density. J. Neural. Eng. 6:14001.  PM:19104141. PMC2679226 (First indication of a logarithmic relationship between synapse density and spike rate, relevant to computational design).

90.  Brewer, G.J., Boehler, M.D., Ide, A.N., Wheeler, B.C. 2009.  Chronic electrical stimulation of cultured hippocampal networks increases spontaneous spike rates.  J. Neurosci. Meth. 184: 104-109. PM:19666055  PMC2753692.pdf (Most neuronal networks develop without external stimulation.  A more natural development with chronic inputs results in a more active network.)

95.  Ide, A.N., Andruska, A., Boehler, M., Wheeler, B.C., Brewer, G.J. 2010. Chronic network stimulation enhances evoked action potentials, J. Neural Eng. 7, 16008 PM:20083862.  PMCID: 20083862

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Text Box: Spikes of activity from neurons over circular black electrodes (left) occur in clusters of bursts (middle) with individual spikes evident (right).

 

 

 

103. Boehler, M.D., Leondopulos, S.S., Wheeler, B.C., Brewer, G.J.  2012. Hippocampal networks on reliable patterned substrates. J. Neurosci. Meth. 203:344-353.

Text Box: Small oscillations in the gamma range (40 Hz) may stimulate spikes Text Box:  105. Leondopulos, S.S., Boehler, M.D., Wheeler, B.C., Brewer, G.J.  2012. Chronic stimulation of cultured neural networks boosts oscillatory activity in the beta and theta frequencies, J. Neural Eng. 9 026015 doi:10.1088/1741-2560/9/2/026015.  PM:22361724

 

 

 

108. Brewer, GJ, Boehler, MD, Leondopulos, S, Pan, L, Alagapan, S, DeMarse, TB, Wheeler, BC. 2013.  Toward a self-wired active reconstruction of the hippocampal trisynaptic loop: DG-CA3.  Frontiers in Neural Circuits, in press.

 

Neuroscience of Aging and Alzheimer Disease

22. Brewer, G.J. and Ashford, J.W.  1992.  Human serum stimulates Alzheimer markers in cultured hippocampal neurons.  J. Neurosci. Res. 33:355-369. PM:1335088 (AD has systemic markers).

38.      Yang Y., Quitschke, W.W. and Brewer, G. J.  1998.  Upregulation of amyloid precursor protein gene promoter in rat primary hippocampal neurons by phorbol ester, IL-1 and retinoic acid, but not by reactive oxygen species.  Molec. Brain Res. 60:40-49.PM:9748493 (Genetic control of amyloid by inflammatory mediators).

40.      Brewer, G.J.  1998. Age-related toxicity to lactate, glutamate, and beta-amyloid in cultured adult neurons.  Neurobiol. Aging 19:561-568. PM:10192215 (Seminal basis for studying brain aging in relation to Alzheimer’s disease).

44.      Yang, Y., Quitschke, W.W., Vostrov, A.A. and Brewer, G.J.  1999.  CTCF is essential for upregulating expression from the amyloid precursor protein promoter during differentiation of primary hippocampal neurons. J. Neurochem. 73:2286-2298. PM:10582586 (Genetic control of amyloid expression).

55.      Viel, J.J., McManus, D.J., Smith, S.H. and Brewer, G.J. 2001.  Age and concentration-dependent neuroprotection and toxicity by TNF in cortical neurons from beta-amyloid.  J. Neurosci. Res. 64:454-465.PM:11391700  (Early identification of a role of inflammatory mediator TNF in exacerbating beta-amyloid toxicity in AD)

59.      Cady, C., Evans, M.S. and Brewer, G.J. 2001. Age-related differences in NMDA responses in cultured rat hippocampal neurons. Brain Res, 921:1-11. PM:11720706

60.      Nathan, B.P., Jiang, Y., Wong, G.K., Shen, F., Brewer, G. and Struble, R.G. 2002.  Apolipoprotein E4 inhibits and apolipoprotein E3 promotes neurite outgrowth in cultured adult mouse cortical neurons through the low-density lipoprotein receptor-related protein. Brain Res. 928:96-105.PM:11844476

62.      Patel, J.R., Brewer, G.J. 2003.  Age-related changes in neuronal glucose uptake in response to glutamate and beta-amyloid J. Neurosci. Res.72:527-536.PM:12704814 (Neuron glucose transport declines with age to limit energy production, but the deficit is reversible).

69.      Brewer, G.J., Lim, A., Capps, N.G., Torricelli, J.R. 2005. Age-related calcium changes, oxyradical damage, caspase activation and nuclear condensation in hippocampal neurons in response to glutamate and beta-amyloid, Exp. Gerontol., 40:426-437.PM:15919595

72.      Brewer,G.J.; Reichensperger,J.D.; Brinton,R.D. 2006.  Prevention of age-related dysregulation of calcium dynamics by estrogen in neurons, Neurobiology of Aging 27:306-317.  PM:15961189 (Landmark age-related dysregulation of neuron calcium dynamics and reversal by estrogen).

74.      Parihar, M.S., Brewer, G.J. 2007a.  Mitoenergetic failure in Alzheimer disease. Am J Physiol Cell Physiol. 292 C8-C23 PM:16807300;  http://ajpcell.physiology.org

75. Parihar, M.S., Brewer, G.J.  2007b. Simultaneous age-related depolarization of mitochondrial membrane potential and increased mitochondrial ROS production correlate with age-related glutamate excitotoxicity in rat hippocampal neurons, J. Neuroscience Res. 85:1018-1032. PM:17335078. (First indication of age-related depolarization of neuron mitoochondria and relationship to oxyradical production).

81.      Joseph, J.A., Carey, A., Brewer, G.J., Neuman, A., Lau, F.C., Fisher, D.R. 2007.  Dopamine and Aβ-induced stress signaling and decrements in Ca2+ buffering in primary neonatal hippocampal cells are antagonized by blueberry extract.  J. Alzheimer Dis. 11:433-446.  PM:17656822

84.      Parihar, M.S., Kunz, E., Brewer, G.J.  2008. Age-related decreases in NAD(P)H and glutathione cause redox declines before ATP loss during glutamate treatment of hippocampal neurons.  J. Neurosci. Res. 86:2339-2352 PM:18438923. (First evidence for age-related deficits in redox state).

85.      Patel, J.R., Brewer, G.J. 2008.  Age-related changes to TNF receptors affect neuron survival in the presence of beta-amyloid.  J. Neurosci. Res. 86:2303-2313 PM:18418902. PMC2562897 (Further evidence for age-related role of inflammatory cytokine TNF in synergistic enhancement of beta-amyloid toxicity.)

87.      Patel, J.R., Brewer, G.J. 2008.  Age-related differences in NFκB translocation and Bcl-2 ratio caused by TNFα and Abeta42 promote survival in middle-age neurons and death in old neurons, Exp. Neurol. 213:93-100. PM:18625500 PMC2597588 (Molecular basis for age-related toxicity of TNF combined with beta-amyloid).

89.      Jones, T.T. and Brewer, G.J. 2009. Critical age-related loss of cofactors of neuron cytochrome C oxidase reversed by estrogen.  Exp. Neurology, 215:212-219. PM:18930048 PMCID:3018880 (First identification of an age-related molecular deficit in neuron mitochondria AND the potential for rapid reversal).

91.      Brewer, G.J. Lindsey, A.L. Kunz, E.Z.  Torricelli, J.R. Neuman, A. Fisher, D.R. Joseph, J.A. 2010. Age-related toxicity of β-amyloid associated with increased pERK and pCREB in primary hippocampal neurons: reversal by blueberry extract. J. Nutr. Biochem.  21:991-998. PM:19954954  PMCID: 2891857 (Clear age-related induction of a stress response by phytochemicals in blueberries to protect against beta-amyloid toxicity.)

92.  Brewer, G.J.  2010. Why vitamin E therapy fails for treatment of Alzheimer disease.  J. Alzheimer’s Dis. 19: 27-30. PM: 20061623   PMCID: 3023173

Text Box:  93.  Jones, T.T. and Brewer, G.J.  2010.  Age-related deficiencies in complex I endogenous substrate availability and reserve capacity of complex IV in cortical neuron electron transport.  Biochim. Biophys. Acta Bioenergetics, 1797:167-176. PMCID: PMC2812684.  PMCID: 2812684 (Identification of the sites of age-related dysfunction in mitochondria).

96.      Brewer, GJ. (2010) Epigenetic oxidative redox shift (EORS) theory of aging unifies the free radical and insulin signaling theories, Exp Gerontol.45:173-179. PM:19945522. PMCID: 2826600 (Potential new landmark theory of aging).

98.  Joseph, J.A., Shukitt-Hale, B., Brewer, G.J., Weikel, K.A., Kalt, W., Fisher, D.R. 2010. Differential protection among fractionated blueberry polyphenolic families against DA-, Aβ42 and LPS-induced decrements in Ca2+ buffering in primary hippocampal cells. J. Agriculture Food Chem. 58:8196-8201. PM:20597478.   (Polyphenolic fractions of blueberries are less effective than the whole for neuroprotection.)

99.  Struble, R.G., Ala, T., Patrylo, P.R., Brewer, G.J., Yan, X.X.  2010. Is brain amyloid production a cause or a result of dementia of the Alzheimer type?, J. Alz. Dis., 22:393-399. PM:20847431, PMCID: 3079347

100. Parihar, MS, Brewer, G.J. 2010.  Amyloid beta as a modulator of synaptic plasticity, J. Alzheimer’s Dis. 22:741-763. PM:20847424, PMCID: 3079354 (Essential normal role of A-beta is emphasized to raise caution about anti-amyloid therapies.)

101.  Barnett, A, Brewer GJ.  2011. Autophagy in aging and Alzheimer’s disease: pathologic or protective?  J. Alzheimer’s Dis. 25: 385-394.PM:21422527

104. Walker, MW, LaFerla, F; Oddo, S, and Brewer, GJ. Reversible early age epigenetic histone modifications in a mouse model of Alzheimer’s disease: effects on BDNF expression.  AGE, 35:519-531. Springer doi. PM:22237558, (Major epigenetic changes in histone acetylation and methylation occur early in aging and in 3xTg-AD mice, most downloaded paper in Age 2012)

106. Ghosh, D; LaFerla, F; Oddo, S., Brewer, GJ Oxidized redox state in cultured hippocampal neurons precedes cognitive losses and macromolecular ROS damage in 3xTg-AD mice.  J. Neurosci. 32:5821-5832.  PM:22539844, PMCID: 3376759  (An early change in redox state, a metabolic shift, may be pathogenic.)

107. Ghosh, D., Brewer, GJ, 2013. Dual energy precursor and Nrf2 activator treatment additively improves redox glutathione levels and neuron survival in aging and Alzheimer mouse neurons upstream of ROS, Neurobiol. Aging 35:179-190. (Redox state is upstream of ROS for neurodegeneration and redox state can be targeted for neuroprotection by boosting NADH synthesis and redox transcription.)

 

 

 

Advances in Neuron Culture

23.      Brewer, G.J., Torricelli, J.R., Evege, E.K. and Price, P.J.  1993.  Optimized survival of hippocampal neurons in B27-supplemented Neurobasal™, a new serum-free medium combination.  J. Neurosci. Res. 35:567-576. PM:8377226 (The first culture medium optimized for neurons.  Remains the #1 neuron culture medium with world-wide distribution through license to Invitrogen)

24.      Brewer, G.J., Torricelli, J.R., Evege, E.K. and Price, P.J.  1994. Neurobasal™ Medium/B27 supplement:  a new serum-free medium combination for survival of neurons.  Focus 16:(1)6-9.

25.      Brewer, G.J.  1995. Serum-free B27/Neurobasal medium supports differentiated growth of neurons from the striatum, substantia nigra, septum, cerebral cortex, cerebellum and dentate gyrus.  J. Neurosci. Res. 42:674-683.  PM:8600300 (Medium optimized for hippocampal neurons supports the growth of neurons from many brain regions).

28.  Brewer, G.J. and Price, P.J. 1996. Viable cultured neurons in ambient carbon-dioxide and hibernation storage for a month.  Neuroreport  7:1509-1512. PM:8856709 (Invention that enabled the isolation of adult neurons from brain and shipping live neurons world-wide.)

30.      Brewer, G.J. 1997. Isolation and culture of adult rat hippocampal neurons of any age.  J. Neurosci. Meth. 71:143-155.  PM:9128149 (First demonstration of significant viable recovery of adult neurons).

34.      McManus, D.G. and Brewer, G.J. 1997. Culture of neurons from postmortem rat brain.  Neurosci. Lett. 224:193-196. PM:9131669  (Relationship of post-mortem interval to neuron recovery.)

37.      Evans, M.S., Collings, M. and Brewer, G.J. 1998. Electrophysiology of embryonic, adult and aged rat hippocampal neurons in serum-free culture.  J. Neurosci. Meth. 79:37-46. PM:9531458

39.  Brewer G.J., Deshmane S. and Ponnusamy, E.  1998.  Precocious axons and improved survival of rat hippocampal neurons on lysine-alanine polymer substrates.  J. Neurosci. Meth. 85:13-20.PM:9874136

43.  Brewer, G.J.  1999. Regeneration and proliferation of embryonic and adult hippocampal neurons.  Exp. Neurology 159:237-247. PM:10486191  (Early work showing the plasticity of dedifferentiation and the induction of neuron multiplication.)

45.  Brewer, G.J. June 1, 1999. Alternating lysine-alanine copolymer substrate for promoting neuron survival and axon growth.  United States Patent 5,908,783.

47.      Brewer, G.J. and Wallimann, T.W.  2000. Protective effect of the energy precursor creatine against toxicity of glutamate and beta-amyloid in rat hippocampal neurons.  J. Neurochem. 74:1968-1978. PM:10800940

52.      Brewer, G.J. and Price, P.J. January 30, 2001. Culture medium for maintaining neural cells in ambient atmosphere, U.S. Patent 6,180,404.  (Basis for Dr. Brewer’s company, BrainBits and source of $ millions of income to the University).

53.      Viel, J.J., McManus, D.J. and Brewer, G.J. 2001.  Temperature and time interval for culture of postmortem neurons from adult rat cortex.  J. Neurosci. Res. 64:311-321.PM:11340637

56.  Brewer G.J., Espinosa, J., McIlhaney, R., Pencek, T, Kesslak, J.P., Cotman, C.W., Viel, J.J., and McManus, D.Q.  2001. Culture and regeneration of human neurons after brain surgery. J. Neurosci. Meth. 107:15-23.PM:11389937 

61.      Brewer, G.J., Espinosa, J.A., Struble, R.G. 2003. Effect of Neuregentmnutrient medium on survival of cortical neurons after aspiration lesion in rats.  J. Neurosurgery 98:1291-1298.PM:12816277 (Clear benefit of nutrient medium during brain surgery).

65.      Viel, J.J., McManus, D.J. and Brewer, G.J. 2004.  Postmortem effect of pentobarbitol anaesthetic, Brain Res. 1009:219-222. PM:15120600

66.      Brewer, G.J., Jones, T.T., Walliman, T., Schlattner, U. 2004 Higher respiratory rates and improved creatine stimulation in brain mitochondria isolated with anti-oxidants, Mitochondrion 4:49-57 PM:16120374

78.      Brewer, G.J., Le Roux, P.D. 2007. Human primary brain tumor cell growth inhibition is serum-free medium optimized for neuron survival, Brain Res. 1157:156-166. PM:17537410

79.  Brewer, G.J., Torricelli, J.R.  2007.  Isolation and culture of adult neurons and neurospheres, Nature Protocols 2:1490-1498. PM:17545985  2007 Brewer Nat Prot.pdf  (popular protocol that elicits inquiries every week).