Neurological and Neurodegenerative Disorders

The direct and indirect cost for care of patients with neurological and neurodegenerative disorders exceeds $200 billion annually in the USA alone. MCIN members are investigating a) the pathology and pathogenesis of Alzheimer's disease and diabetic encephalopathy, b) the role of inflammation in the progression of Parkinson's disease, and the contribution of the basal ganglia to cognitive functions that become impaired in this disease, c) the role of aquaporins in water homeostasis that is disrupted and may be pathogenic in demyelinating diseases, and d) how photoreceptor loss associated with degenerative retinal disease may cause remodeling of the retinal circuitry.

 

Bamburg: Cofilin-actin rods that form in axons and dendrites of stressed neurons are a recently recognized pathology of human Alzheimer disease. We study all aspects of the formation and effects of these rods on neuronal survival and function and are currently working to develop ways to reduce or eliminate rods. Animal models and organotypic slice cultures are used.

Davis RC, Maloney MT, Minamide LS, Flynn KC, Stonebraker MA, Bamburg JR. Mapping cofilin-actin rods in stressed hippocampal slices and the role of cdc42 in amyloid β-induced rods. J Alzheimers Dis 18, 35-50 (2009). PMID: 19542631

Bamburg JR, Bloom GS. Cytoskeletal pathologies of Alzheimer disease. Cell Motil Cytoskel. 66, 635-649 (2009). PMID: 19479823

Whiteman IT, Gervasio OL, Cullen KM, Guillemin GJ, Jeong EV, Witting PK, Antao ST, Minamide LS, Bamburg JR*, Goldsbury C*. (*co-corresponding authors) Activated ADF/cofilin sequesters phosphorylated microtubule associated protein during assembly of Alzheimer-like neuronal cytoskeletal striations. J Neurosci 29, 12994-13005 (2009) PMID: 19828813

 

Ishii: We are testing the novel hypotheses that a decline in insulin and insulin-like growth factors (IGFs) activities play a major role in the pathogenesis of diabetic peripheral neuropathy, as well as brain atrophy associated with dementia in both diabetes and Alzheimer's disease, by mechanisms predominantly unrelated to glucose regulation. Diabetes is a major risk factor for Alzheimer's disease.

Ishii DN, Lupien SB Insulin-Like Growth Factor Replacement Therapy for Diabetic neuropathy: Experimental Basis. Exptl Diabesity Res 4, 257-269 (2003). PMID: 14668048

Serbedzija P, Madl JE, Ishii DN. Insulin and IGF-I Prevent Brain Atrophy and DNA Loss in Diabetes. Brain Research 1303, 179-194 (2009). PMID: 19781531

 

Rash: We are investigating the role of aquaporins (AQP1 and AQP4) in water homeostasis in rodent CNS, as well as the role of autoimmune destruction of AQP4 in human neuromyelitis optica. My recent review of altered water homeostasis and disruption of potassium siphoning in NMO provides a new model for better understanding several demyelinating diseases of the CNS.

Frydenlund DS, Bhardwaj A, Otsuka T, Mylonakou MN, Yasumura T, Davidson KGV, Zeynalov E, Skare O, Laake P, Haug FM, Rash JE, Agre P, Ottersen OP, Amiry Moghaddam M. Temporary loss of perivascular aquaporin-4 in neocortex after transient middle cerebral artery occlusion in mice. Proc. Natl.Acad. Sci. (USA) 103:13532-13536 (2006). PMID: 16838871

Rash, JE. Molecular disruptions of the panglial syncytium block potassium siphoning and axonal saltatory conduction: pertinence to neuromyelitis optica and other demyelinating diseases of the central nervous system. Neuroscience (in press) Oct 20, 2009 [Epub ahead of print] PMID: 19850107

 

Seger: The Seger lab studies how the basal ganglia contribute to learning and cognition. The basal ganglia are affected in many neurological and psychiatric disorders (e.g., Parkinson's disease and addiction); our research has translational implications for understanding the cognitive impairments in these disorders.

Seger CA, Cincotta CM. The roles of the caudate nucleus in human classification learning. J Neuroscience 25, 2541-2551 (2005). PMID: 15772354

Seger CA. How do the basal ganglia contribute to categorization? Their roles in generalization, response selection, and learning via feedback. Neurosci Biobehav Rev 32: 265-278 (2008). PMID: 17919725

 

Tjalkens: Neuroinflammation influences the progression of Parkinson's disease (PD) and other neurodegenerative disorders but there are currently no approved therapies to block the production of inflammatory mediators by activated microglia and astrocytes. We are examining signaling mechanisms underlying inflammatory gene regulation in glial cells in order to develop better therapeutics to interdict neuroinflammation in PD and related neurodegenerative diseases.

Carbone DA, Popichak KA, Moreno JA, Safe S, Tjalkens RB. Suppression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nitric oxide synthase 2 expression in astrocytes by a novel diindolyl methane analog protects striatal neurons against apoptosis. Mol Pharmacol 75. 35-43 (2009). PMID: 18840677.

Tjalkens RB, Liu X, Mohl B, Wright T, Carbone DL, Moreno JA, Safe S. The PPAR-γ agonist 1,1-bis(3'-indolyl)-1-(p-trifluoromethylphenyl)methane suppresses manganese-induced production of nitric oxide in astrocytes and inhibits apoptosis in co-cultured PC12 cells. J Neurosci. Res 86, 618-629 (2008). PMID: 18041089.

 

Vigh: We are interested in changes in the retinal circuitry triggered by photoreceptor loss in retinal degenerative diseases such as age-related macular degeneration (AMD) or retinitis pigmentosa (RP). Currently, we are working on establishing an inducible model of retinal degeneration in fish.