Daniel Alkon, MD
Toyota Chair in Neurodegenerative Disease, Scientific Director and Professor
Blanchette Rockefeller Neurosciences Institute
Dr. Alkon’s laboratory at the Blanchette Rockefeller Neuroscience Institute conducts multidisciplinary research on the molecular and biophysical mechanisms of associative memory and memory dysfunction in psychiatric and neurological disorders, particularly Alzheimer’s disease. Over the years, Dr. Alkon and his colleagues first identified molecular mechanisms of memory that were responsible for classical conditioning of the nudibranch mollusk Hermissenda. They then demonstrated that these molecular mechanisms were conserved across evolution, providing a basis for memory-specific changes for synaptic function in a variety of animal species and associative learning paradigms such as rabbit nictitating membrane conditioning, rat spatial maze learning, and rat olfactory discrimination learning. Subsequently, they have discovered a convergence of memory-specific molecular and synaptic functions with the pathophysiology of Alzheimer’s disease, particularly involving biochemical cascades in which the isozymes of PKC play a central role. PKC activators, for example, phosphorylate the mRNA stabilizing proteins (HuD, HuR) during associative learning. The mRNA stabilizing proteins then move into the dendritic tree to stabilize and regulate an ensemble of synaptic remodeling proteins such as GAP43, BDNF, IGF, and NGF. Similarly, memory-specific activation of PKC isozymes (e.g. α, ε) activates additional pathways to control learning specific protein synthesis via the NFκB and CREB pathways.
These same pathways are targeted by toxic Aβ elevated in Alzheimer’s tissues to cause the synaptic loss characteristically demonstrated at autopsy and that correlates with the dementia shown by patients clinically. Thus, the convergence of molecular pathways of memory and the pathologic pathways responsible for neuro-degeneration has provided a whole new strategy for diagnosis and treatment in our aging population. Drugs developed and/or tested at BRNI, one, Bryostatin, recently FDA approved for Phase II trial, show remarkable efficacy inducing new synaptic growth in fully differentiated nervous systems, for rescuing drying neurons, and for the normalization of Aβ and amyloid plaques. These new findings on associative memory mechanisms are guiding development of peripheral biomarker diagnostics and drug discovery with the potential to treat the loss of synapses and to prevent neuronal death in neuro-degenerative disorders (e.g. Alzheimer’s disease), stroke, traumatic brain injury, mental retardation, and attention-deficit disorders.
Dr. Alkon received his undergraduate degree in chemistry in 1965 at the University of Pennsylvania, where, with post-graduate studies in physical chemistry, he began his career in biomedical research. After earning his M.D. at Cornell University and finishing an internship in medicine at the Mt Sinai Hospital in New York, he joined the staff of the National Institutes of Health where during his 30 year career he became a medical Director in the U.S. Public Health Service at the NINDS and Chief of the Laboratory of Adaptive Systems. Dr. Alkon then became the founding Scientific Director of the Blanchette Rockefeller Neurosciences Institute and occupies the Toyota Chair in Neuroscience at the Institute. He is also a Professor at BRNI and a Professor of Neurology at West Virginia University.
As an internationally recognized pioneer in research on brain-based neural networks and the molecular basis of memory, he has authored hundred of scientific articles as well as several books including Memory Traces in the Brain by Cambridge University Press, and the popular book Memory’s Voice by Harper Collins.
1961-1965 Four Year Mayor’s Scholarship and General Honors Program,
University of Pennsylvania
1978, 1987 Friday Evening Lecturer, Marine Biological Laboratory
1981 Public Health Service Commendation Medal
1986 Outstanding Science Medal of the United States Public Health Service
1995 Julius Axelrod Distinguished Lecturer in Neuroscience
of the Raymond and Beverly Sackler Foundation
2006 Toyota Chair in Neurodegenerative Disease Research
Selected Peer-reviewed Publications:
Crow TJ, Alkon, D.L.: Associative behavioral modification in Hermissenda: Cellular correlates. Science 209: 412-414, 1980.
Farley J, Alkon, D.L.: Neural organization predicts stimulus specificity for a retained associative behavioral change. Science 210: 1373-1375, 1980.
Alkon, D.L.: Membrane depolarization accumulates during acquisition of an associative behavioral change. Science 210: 1375-1376, 1980.
Neary JT, Crow T, Alkon, D.L.: Change in a specific phosphoprotein band following associative learning in Hermissenda. Nature 293: 658-660, 1981.
Alkon, D.L., Lederhendler I, Shoukimas JJ: Primary changes of membrane currents during retention of associative learning. Science 215: 693-695, 1982.
Alkon, D.L.: Learning in a marine snail. Scientific American 249: 70-84, 1983.
Farley J, Richards WG, Ling LJ, Liman E, Alkon, D.L.: Membrane changes in a single photoreceptor cause associative learning in
Hermissenda. Science 221: 1201-1203, 1983.
Alkon, D.L.: Calcium-mediated reduction of ionic currents: A biophysical memory trace. Science 226: 1037-1045, 1984.
Lederhendler I, Gart S, Alkon, D.L.: Classical conditioning in Hermissenda: Origin of a new response. J Neurosci. 6:(5): 1325-1331, 1986.
Bank B, DeWeer A, Kuzirian AM, Rasmussen H, Alkon, D.L.: Classical conditioning induces long-term translocation of protein kinase C in rabbit hippocampal CA1 Cells. Proc Natl Acad Sci USA 85: 1988-1992, 1988.
Alkon, D.L., Rasmussen H: A spatial-temporal model of cell activation. Science 239: 998-1005, 1988.
LoTurco JL, Coulter DA, Alkon, D.L.: Enhancement of synaptic potentials in rabbit CA1 pyramidal neurons following classical conditioning. Proc Natl Acad Sci USA 85(5): 1672-1676, 1988.
Alkon, D.L.: Memory storage and neural systems. Scientific American 260: 42-50, 1989.
Olds JL, Anderson M, McPhie DL, Staten L, Alkon, D.L.: Imaging of memory-specific changes in the distribution of protein kinase c in the hippocampus. Science 245: 866-869, 1989.
Nelson T, Collin C, Alkon, D.L.: Isolation of a G protein that is modified by learning and reduces potassium currents in Hermissenda. Science 247: 1479-1483, 1990.
Alkon, D.L., Blackwell KT, Barbour GS, Rigler AK, Vogl TP: Pattern recognition by an artificial network derived from biological neuronal systems. Biol Cybern 62: 363-376, 1990.
Collin C, Papageorge AG, Lowy DR, Alkon, D.L.: Early enhancement of calcium currents by H-ras oncoproteins injected into Hermissenda neurons. Science 250: 1743-5, 1990.
Etcheberrigaray R, Ito E, Oka K, Tofel-Grehl B, Gibson GE, Alkon, D.L.: Potassium channel dysfunction in fibroblasts identifies patients with Alzheimer’s disease. Proc Natl Acad Sci USA 90: 8209-13, 1993.
Etcheberrigaray R, Ito E, Kim S, Alkon, D.L.: Soluble β-amyloid induction of Alzheimer’s phenotype for human fibroblast K+ channels. Science 264: 276-9, 1994.
Schreurs BG, Tomsic D, Gusev, PA, Alkon, D.L.: Dendritic excitability microzones and occluded long-term depression after classical conditioning of the rabbit’s nictating membrane response. J Neurophysiol. 77: 86-92, 1997.
Ascoli GA, Luu KX, Olds JL, Nelson TJ, Gusev PA, Bertucci C, Bramanti E, Raffaelli A, Salvadori P, Alkon, D.L.: Secondary structure and Ca2+-induced conformational change of Calexcitin, a learning-associated protein. J Biol Chem 272: 24771-24779, 1997.
Favit A, Grimaldi M, Nelson TJ, Alkon, D.L.: Alzheimer’s-specific effects of soluble β-amyloid on protein kinase C-α and -γ degradation in human fibroblasts. Proc Natl Acad Sci USA 10:5562-5567, 1998.
Meiri N, Sun MK, Segal Z, Alkon, D.L.: Memory and long-term potentiation (LTP) dissociated: normal spatial memory despite CA1 LTPL elimination with Kv1.4 antisense. Proc Natl Acad Sci USA 95:15037-15042, 1998.
Alkon, D.L., Nelson T, Zhao W, Cavallaro S: Time domains of neuronal Ca2+ signaling and associative memory: steps through a calexcitin, ryanodine receptor, K+ channel cascade. Trends in Neuroscience 21:529-537, 1998.
Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, Alkon, D.L.: Brain insulin receptors and spatial memory: Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem. 274: 34893-34902, 1999.
Quattrone A, Pascale A, Nogues Z, Zhao W, Gusev P, Pacini A, Alkon, D.L.: Posttranscriptional regulation of gene expression in learning by the neuronal ELAV like mRNA-stabilizing proteins. Proc Natl Acad Sci USA 98: 11668-73, 200l.
Sun MK, Alkon, D.L.: Carbonic anhydrase gating of attention: memory therapy and enhancement. Trends in Pharmacol Sci. 23: 2, 83-89, 2002.
Zhao WQ, Ravindranath L, Mohamed AS, Zohar O, Chen CH, Lyketsos CG, Etcheberrigaray R, Alkon, D.L.: MAP kinase signaling cascade dysfunction specific to Alzheimer’s disease in fibroblasts. NeuroBiol Disease, 11: 166-183, 2002.
Cavallaro S, D'Agata V, Manickam P, Dufour F, Alkon D: Memory-specific temporal profiles of gene expression in the hippocampus. Proc Natl Acad Sci USA, 99:16279-16284, 2002.
Zhao WQ, Feng C. Alkon, D.L.: Impairment of phosphatase 2A contributes to the prolonged map kinase phosphorylation in Alzheimer's disease fibroblasts. NeuroBiol Dis. 14:458-469, 2003.
Etcheberrigaray R, Tan M, Dewachter I, Kuiperi C, Van der Auwera I, Wera S, Qiao L, Bank B, Nelson TJ, Kozikowski AP, Van Leuven F, Alkon, D.L.: Therapeutic effects of PKC activators in Alzheimer’s disease transgenic mice. Proc Natl Acad Sci USA 101(30): 11141-11146, 2004.
Alkon, D.L., Epstein H, Kuzirian A, Bennett, MC, Nelson T.: Protein synthesis required for long-term memory is induced by PKC activation on days before associative learning. Proc Natl Acad Sci USA 102(45): 16432-16437, 2005.
Khan TK, Alkon, D.L.: An internally controlled peripheral biomarker for Alzheimer’s disease: Erk1 and Erk2 responses to the inflammatory signal bradykinin. Proc Natl Acad Sci USA 103 (35): 13203-13207, 2006.
Alkon, D.L., Sun, M.-K. and Nelson T.J.: PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer’s disease. Trends in Pharmacol. Sci. 28: 2, 51-60, 2007.
Hongpaisan J, and Alkon, D.L.: A structural basis for enhancement of long-term associative memory in single dendritic spines regulated by PKC. Proc Natl Acad Sci USA 104 (49): 19571-19576, 2007.
Sun, M.-K., Hongpaisan, J., Nelson, T.J. and Alkon D.L. Post-stroke neuronal rescue and synaptogenesis mediated in vivo by PKC in adult brains. Proc. Natl. Acad. Sci. USA 105: 13620-13625, 2008.
Nelson TJ and Alkon DL: Neuroprotective versus tumorigenic protein kinase C activators. Trends Biochem Sci. Mar; 34(3):136-45. 2009
Nelson TJ, Cui C, Luo Y, Alkon DL Reduction of beta-amyloid levels by novel PKC(epsilon) activators. J Biol Chem.;284(50):34514-21., 2009.