I have long been interested in the biological bases of learning and memory. My current research focuses on the role of metals in normal memory and in Alzheimer's disease (AD). Zinc, iron and copper are all elevated in the plaques found in the brains of people with AD. The images below show increased metal concentrations in amyloid plaques and vascular deposits. These sections were obtained using synchrotron X-ray fluorescence at the Brookhaven National Laboratory.
I maintain a mouse colony at George Mason University with transgenic mice that carry an APP mutation, so that they develop plaques. We have looked at a model of early onset-AD and are currently developing a new model for late-onset AD. We are examining the effect on behavior and on plaque development of raising these mice on different levels of metals in the drinking water. We find that both zinc and iron significantly impaired spatial memory in mice modeling early onset AD, but copper partially remediated the zinc effect.
We have also shown that increased zinc impairs both spatial memory and the ability to learn that a stimulus is no longer fearful in normal mice and rats. The latter effect may be a model for post-traumatic stress disorder (PTSD). These memory deficits are partially alleviated by giving small amounts of copper. Zinc supplements are widely used, and zinc, with copper, is recommended as a treatment for age-related macular degeneration (AMD). We have also begun to examine metal levels in the eyes of people who had AMD and find increased zinc in the drusen which are characteristic of AMD.
Both PhD and MA students work in the lab. My work has appeared in journals such as Pharmacology, Biochemistry and Behavior; Physiology and Behavior; J. Histochemistry and Cytochemistry; Experimental Eye Research; and J. Alzheimer’s Disease (in press).
Students in my lab have backgrounds in psychology, biology, biochemistry, and computer science. Here I am with some of my students at the 2006 Society for Neuroscience meeting in Atlanta.
Selected Papers on the Role of Metals in Memory, Alzheimer's Disease, and Macular Degeneration
Alterations in fear response and spatial memory in pre- and post- natal zinc supplemented rats: remediation by copper. A. M. Railey, T. L. Micheli, P. B. Wanschura, J. M. Flinn. Physiology and Behavior, 11;100(2):95-100, 2010.
The effects of enhanced zinc on spatial memory and plaque formation in transgenic mice. D. H. Linkous, P. A. Adlard, P. B. Wanschura, K. M. Conko, and J. M. Flinn. J, Alzheimer's Disease. 18(3) 541-551, 2009.
Evidence that the ZNT-3 protein controls the total amount of elemental zinc in synaptic vesicles. D.H. Linkous, J.M. Flinn, J.Y. Koh, A. Lanzirotti, P. Bertsch, B.F. Jones and C.J. Fredrickson. J Histochem Cytochem. Jan;56(1):3-6, 2008.
Abnormal flash visual evoked potentials in malnourished infants: An evaluation using principal component analysis. C.G. McDonald, A.B, Butler, C. Joffe and J.M. Flinn. Clinical Neurophysiology . 118(4):896-900, 2007
High concentration of zinc in sub-retinal deposits. I. Lengyel, J.M. Flinn, T. Peto, D.H. Linkous, K. Cano, A.C. Bird, A. Lanzirotti, C.J. Frederickson and F.G.G.M. van Kuijk. Experimental Eye Research. 84(4):772-80, 2007
Elemental mapping and quantitative analysis of Cu, Zn, and Fe in rat brain sections by laser ablation ICP-M. S. B. Jackson, S. Harper, L. N. Smith, J. M. Flinn. Analytical and Bioanalytical Chemistry. 384(4) 951-7. 2006.
Effects of enhanced zinc and copper in drinking water on spatial memory and fear conditioning. L.D. Chrosniak, L.N Smith, J.M., Flinn, C. McDonald, and B.F. Jones., J. Geochemical Exploration.88(1-3): 91-94, 2006.
Enhanced zinc consumption causes memory deficits and increased brain levels of zinc. J.M. Flinn, D. Hunter, D.H. Linkous, A. Lanzirotti, L.Smith, J.J. Brightwell, and B.F. Jones. Physiology and Behavior. 83 (5) 793-803, 2005.
Synchrotron Infrared Spectroscopy at NSLS beamline U2B. N.S. Marinkovic, M.R.Chance, K.M. Dokken, L.C. Davis, D.H. Linkous, and J.M. Flinn. American Laboratory. 23(1) 12-13, 2005.
Differential effects of zinc association in drinking waters on spatial memory. D.H. Linkous, L.N. Smith, K.M. Conko, B.F. Jones and J.M. Flinn. (2004) Metal Ions in Biology and Medicine. 8: 390-395, 2004.
Enhanced Levels of Zinc in Drinking Water Adversely Affect Spatial Learning in Rats. J.M. Flinn, J. Morvan and B.F. Jones. Metal Ions in Biology and Medicine. 6:450-452, 2000.
Selected Abstracts (since 2005)
Differences in behavior and amyloid plaque deposition in Tg 2576 mice and Wt 2576 mice, after chelation of iron by Feralex injection. A.J. Burns, T.L. Micheli, C.M. Groeber, K.V. Morgan, E.S. Gideons, J.M. Flinn, T.P.A. Kruck, M.E. Percy. Soc. for Neurosci. 36th Annual Mtg.Oct 2007
Alzheimer disease AB plaque formations have significantly more K, Fe, Cu, and Zn than surrounding tissue, detected with microprobe synchrtron X-ray fluorescence. J.M. FDlinn,. J.P. Kesslak, E.Head, K.Cano, A. Lanzirotti, W. Rao, B.F. Jones, P. Bertsch, C. Frederickson, D.H. Linkous. Soc. for Neurosci. 36th Annual Mtg.Oct 2007.
Dietary enhancement of iron, zinc and copper and the effect of on APP tg2576 mice, as assessed through novel object recognition. C.M. Groeber, B.F. Jone, L.D. Chrosniak, J.M. Flinn. Soc. for Neurosci. 36th Annual Mtg.Oct 2007
Zinc related spatial memory impairment in Tg 2576 mice. A.M. Railey, K. Morgan, R. McGarry, P. Wanschura, J.M. Flinn. Soc. for Neurosci. 36th Annual Mtg.Oct 2007.
Dietary enhancement of zinc is associated with the reduction of plaque burden in the Tg 25676 mouse while impairing Morris water maze task acquisition. D.H. Linkous, K.Cano, P. Wanschura, A. Fitzgerald, J.H. Thompson, J. Nemec, A. Stern, B.F. Jones, K. Conko, J.M. Flinn. Soc. for Neurosci. 36th Annual Mtg.Oct 2007.
Effects of dietary enhancement of iron on Aß and behavior in Tg2576 mice. J.H. Thompson, K.E. cano, T.L. Micheli, A.J. Burns, B.F. Jones, P.B. Wanshura, J.M. Flinn. Soc. for Neurosci. 36th Annual Mtg.Oct 2006.
Cognitive effects of long term enhanced dietary zinc consumption, Modulation by copper. A.M. Railey, L.N. Smith, K. Moran, M. Veejay, A, Fitzgerald, T. Micheli, J.M. Flinn, B.F. Jones, L.D. Chrosniak. Soc. for Neurosci. 36th Annual Mtg.Oct 2006.
Effects of dietary enhancement of iron on APP2576 mice assessed through novel object recognition. C.M. Groeber, A.M. Railey, B.F. Jones, L.D. Chrosniak, J.M. Flinn. Soc. for Neurosci. 36th Annual Mtg.Oct 2006.
Synchrotron IR analysis of amyloid conformation in zinc- and iron-treated TgAPP2576 mice. K.E. Cano, J.A. Nemec, N.S. Marinkovic, M.V. Sheridan, D.H. Linkous, B.F. Jones, J.M. Flinn. Soc. for Neurosci. 36th Annual Mtg.Oct 2006.
Zinc and iron have different effects on transgenic mouse behavior. D.H. Linkous, J. Thompson, A. Stern, S. Lee, J. Nemec, P. Wanschura, L.N. Chrosniak, J.M. Flinn. APA 114th Annual Mtg, Washington D.C., 2005.
The effects of enhanced zinc on fear conditioning and extinction. L.N. Smith, L.D.Chrosniak, S.Kumar, A.Zijerdi, C. G.McDonald, J.M.Flinn. APA 114th Annual Mtg, Washington D.C.
Effects of pre- and post-natal dietary consumption of zinc (ZnCO3) on phenotype and Alzheimer-like pathology in APP2576 transgenic mice. K. E. Cano, D. H. Linkous, J.H.Thompson, P.B. Wanschura, and J. M. Flinn. Soc. for Neurosci. 35th Annual Mtg. Nov 2005.
Effects of dietary consumption of zinc and iron on Beta-amyloid conformation using synchrotron infrared microscopy. J. Nemec, N.S. Marinkovic, K.E. Cano, D.H. Linkous, J.M. Flinn & Blair F. Jones. Soc. for Neurosci. 35th Annual Mtg. Nov 2005.
Analysis of zinc and copper in age-related macular degeneration drusen. D. H. Linkous, K. E. Cano, I.Lengyel, F. van Kuijk, A. Lanzirotti, C. J. Frederickson, W.Rao, B. F. Jones, P. Bertsch, & J. M. Flinn.. Soc. for Neurosci. 35th Annual Mtg. Nov 2005.
The following images illustrate some of the research conducted by my lab.
Figure 1. Synchrotron X-ray Fluorescence examining the metal content of plaques in the brains of Alzheimer's patients.
Figure 2. False colour images produced via µXSRF analysis of a mouse neural plaque. Images show iron (Fe, top left), calcium (Ca, top right), zinc (Zn, bottom left), and potasium (K, bottom right).
These images indicate relative metal content within a plaque and surrounding neural tissue taken from a year-old TgAPP2576 mouse displaying AD pathology. Data were collected with a high-intensity synchrotron x-ray light-source. Each image displays its own scalebar, showing the highest counts for that particular image; thus absolute metal concentrations may vary between images.
Figure 3. False-color IR intensity maps (top) showing protein conformation in a plaque (bottom left). The maps indicate α-helix content (top left) and β-pleated sheet content (top right).
These images were obtained through IR imaging using a high-intensity synchrotron light-source. The false colour maps show relative IR spectra for the point indicated by the cross hairs on the maps. These maps show intensity of the α-helix peak and the β-pleated sheet peaks.
Figure 4. Synchrotron X-ray Fluorescence was used to examine the zinc levels in the retinas of patients with age related Macular Degeneration. These retinas are characterized by the presence of drusen, which have high concentrations of zinc.
Fig. 5. Using the Morris Water Maze we have shown that Transgenic mice that model Alzheimer's disease, which have been raised on enhanced levels of zinc in the drinking water, show impaired spatial memory. Enhanced zinc in the diet leads to copper deficiencies and these deficits can be remediated by proper supplementation with copper.
Fig. 6. Rats raised on enhanced levels of zinc in drinking water show enhanced freezing in contextual conditioning and do not extinguish freezing as quickly as normal rats in a cued conditioning situation. These behavioral differences are partially reduced by copper remediation.
Students from my lab and Dr. Robert Smith's lab are enjoying a meal with me at the Hard Rock Cafe in Atlanta after a long day at the Conference Center.
BIOPSYCHOLOGY PROGRAM LINKS
The 32 hour MA rquires a thesis. All courses are open to both MA and PhD students.
The 72 hour PhD focuses on aging, Alzheimer's disease, learning and memory, neuronal modeling and substance abuse,
with an emphasis on animal research. The program also provides strong training in neuroanatomy and statistics.
Society for Neuroscience Posters