Alzheimer Disease; Axons; Dementia; Spinal Cord Injuries; Motor Neuron Disease; Regenerative Medicine
Neural Repair and Neuro-Degeneration
Neurological injury frequently interrupts connections while sparing nerve cells. Spinal Cord Injury (SCI) is the epitome of a disconnection syndrome, in which surviving neural tissue fails to function due to lost communication at the level of injury. For the organism to regain function, new pathways must form by growth of cut or surviving nerve fibers. Unfortunately, the growth of axons and the rearrangement of brain circuitry are extremely limited in the adult brain and spinal cord.
We focus on understanding the molecular pathways that limit fiber growth and functional rewiring of neuronal circuits during health and disease. Axonal growth encompasses both neural plasticity and repair. Technically, we utilize chronic in vivo imaging of neuronal connections, genetic alteration of mice and induction of surgical lesions resembling clinical SCI and Stroke. In particular, we have found that the NogoReceptor (NgR1) pathway mediating myelin inhibition of axonal growth plays a role in titrating anatomical plasticity in the adult CNS.
In Alzheimer's Disease and several other neurodegenerative conditions, nerve cells are lost over time. Molecular contributors to this pathology have been discovered by genetic methods, but their mechanism of action has remained poorly understood. We have focused on defining the pathophysiological action of Amyloid-beta (Aß) peptide oligomers in Alzheimer's Disease, and on the role of secreted Progranulin in Fronto-Temporal Dementia. For both of these molecules, interaction with the specific receptors on the neuronal surface is crucial. We utilize receptor ligand binding assays, expression cloning, electrophysiology, genetics and mouse behavior to study these pathways.
- Haas, L.T., Salazar, S.V., Kostylev, M., Um, J.W., Strittmatter, S.M. Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signaling in Alzheimer’s disease. Brain : a journal of neurology, Dec 14. pii: awv356. [Epub ahead of print] (2015).
- Bhagat, S.M., Butler, S.S., Taylor, J.P., McEwen, B.S., Strittmatter, S.M. Erasure of Fear Memories is Prevented by Nogo Receptor 1 in Adulthood. Mol Psychiatry, Dec 1. doi: 10.1038/mp.2015.179. [Epub ahead of print] (2015).
- Kaufman AC, Salazar SV, Haas LT, Yang J, Kostylev MA, Jeng AT, Robinson SA, Gunther EC, van Dyck CH, Nygaard HB, Strittmatter SM. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Ann Neurol. 77: 953-971 (2015).
- Zou Y, Stagi M, Wang X, Yigitkanli K, Siegel CS, Nakatsu F, Cafferty WB, Strittmatter SM. Gene-Silencing Screen for Mammalian Axon Regeneration Identifies Inpp5f (Sac2) as an Endogenous Suppressor of Repair after Spinal Cord Injury. J Neurosci. 35:10429-10439 (2015).
- Wang X, Lin J, Arzeno A, Choi JY, Boccio J, Frieden E, Bhargava A, Maynard G, Tsai JC, Strittmatter SM. Intravitreal delivery of human NgR-Fc decoy protein regenerates axons after optic nerve crush and protects ganglion cells in glaucoma models. Invest Ophthalmol Vis Sci. 56:1357-1366 (2015).
- Kostylev MA, Kaufman AC, Nygaard HB, Patel P, Haas LT, Gunther EC, Vortmeyer A, Strittmatter SM. Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models. J Biol Chem. 290:17415-17438 (2015).
- Fink, K.L., Strittmatter, S.M., Cafferty, W.B.J. Comprehensive corticospinal labeling with mu-crystallin transgene reveals axon regeneration after spinal cord trauma in ngr1-/- mice. J Neurosci., 35:15403-15418 (2015).
- Nygaard HB, Kaufman AC, Sekine-Konno T, Huh LL, Going H, Feldman SJ, Kostylev MA, Strittmatter SM. Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer's disease mouse model. Alzheimers Res Ther. 7:25 (2015).
- Nygaard HB, Wagner AF, Bowen GS, Good SP, MacAvoy MG, Strittmatter KA, Kaufman AC, Rosenberg BJ, Sekine-Konno T, Varma P, Chen K, Koleske AJ, Reiman EM, Strittmatter SM, van Dyck CH. A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease. Alzheimers Res Ther. 7:35 (2015).
- Siegel CS, Fink KL, Strittmatter SM, Cafferty WBJ. Plasticity of intact rubral projections mediates spontaneous recovery of function after corticospinal tract injury. J Neurosci 35(4):1443-1457 (2015).
- Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H, Kerrisk ME, Vortmeyer A, Wisniewski T, Koleske AJ, Gunther EC, Nygaard HB, Strittmatter SM. Metabotropic Glutamate Receptor 5 is a Co-Receptor for Alzheimer Aß Oligomer Bound to Cellular Prion Protein. Neuron, 79:887-902 (2013).
- Akbik FV, Bhagat SM, Patel RR, Cafferty WBJ, Strittmatter SM. Anatomical Plasticity of Adult Brain is Titrated by Nogo Receptor 1. Neuron, 77:859-866 (2013).
- Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M, Vortmeyer A, Wisniewski T, Gunther EC, Strittmatter SM. Alzheimer Amyloid-ß Oligomer Bound to Post-Synaptic Prion Protein Activates Fyn to Impair Neurons. Nat Neurosci. 15:1227-1235 (2012).
- Wang X, Duffy P, McGee AW, Hasan O, Gould G, Tu N, Harel NY, Huang Y, Carson RE, Weinzimmer D, Ropchan J, Benowitz LI, Cafferty WB, Strittmatter SM. Recovery from chronic spinal cord contusion after Nogo receptor intervention. Ann Neurol. 70:805-821 (2011).
- Hu F, Padukkavidana T, Vægter CB, Brady OA, Zheng Y, Mackenzie IR, Feldman HH, Nykjaer A, Strittmatter SM. Sortilin-Mediated Endocytosis Determines Levels of the Fronto-Temporal Dementia Protein, Progranulin. Neuron, 68:654-667 (2010).
- Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-ß Oligomers. Nature 457:1128-1132 (2009).
- McGee W, Yang Y, Fischer QW, Daw N, Strittmatter SM. Experience-Driven Plasticity Of Visual Cortex Restricted By Myelin And Nogo Receptor. Science 309: 2222-2226 (2005).
- Fournier A, GrandPre T, Strittmatter SM. Identification of a neuronal receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409:341-346 (2001).
- Grandpre T, Nakamura F, Vartanian T, Strittmatter SM. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature, 403: 439-444 (2000).
- Takahashi T, Fournier A, Nakamura F, Wang, LH, Murakami Y, Kalb RG, Fujisawa H, Strittmatter SM. Plexin-neuropilin1 complexes form functional semaphorin-3A receptors. Cell 99: 59-69 (1999).