Research Interests - Gregory J. Brewer October 8, 2013
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. (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).
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.
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.
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).
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. (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. (Improved chemical stability of substrate over periods of weeks).
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.
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. (Identifies proportions of excitatory and inhibitory synapses.)
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. (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. . (Clear role of astroglia to enhance network firing dynamics).
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. .
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. (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:. (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 (Most neuronal networks develop without external stimulation. A more natural development with chronic inputs results in a more active network.)
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.
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
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. (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. (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. (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. (Early identification of a role of inflammatory mediator TNF in exacerbating beta-amyloid toxicity in AD)
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.
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. (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.
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. (Landmark age-related dysregulation of neuron calcium dynamics and reversal by estrogen).
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.. (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.
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 (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 . (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. (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. (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. (Clear age-related induction of a stress response by phytochemicals in blueberries to protect against beta-amyloid toxicity.)
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: . (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. (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. , PMCID: 3079347
100. Parihar, MS, Brewer, G.J. 2010. Amyloid beta as a modulator of synaptic plasticity, J. Alzheimer’s Dis. 22:741-763. , 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. (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. (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. (Invention that enabled the isolation of adult neurons from brain and shipping live neurons world-wide.)
43. Brewer, G.J. 1999. Regeneration and proliferation of embryonic and adult hippocampal neurons. Exp. Neurology 159:237-247. (Early work showing the plasticity of dedifferentiation and the induction of neuron multiplication.)
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).
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.
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. (Clear benefit of nutrient medium during brain surgery).