Thiamine (vitamin B1) deficiency (TD) produces a mild, chronic impairment of oxidative metabolism that models the diminished metabolism and reduced activities of the thiamine-dependent mitochondrial enzymes that occur in brain in several common age-related neurodegenerative disorders. Regionally selective neurodegeneration and activation of astrocytes, microglia and endothelial cells occur in TD and in these diseases. Vascular changes, inflammatory responses, oxidative stress and neuronal death are present in brains from TD mice and in brains from patients who die from common neurodegenerative diseases. A mechanistic sequence of events cannot be discovered in autopsied human brain, but can be studied effectively in experimental animals. Several features of the TD model make it amenable to analysis of the interactions leading to neurodegeneration: 1) The time course of the events leading to neuronal death is prolonged (11 days). 2) The death occurs in a discrete nucleus with a well-defined number of neurons. 3) The model exists in mice so transgenic animals can be used to test mechanism. The proposed experiments will test the following hypothesis: TD-induced abnormafities in metabolism increase neural production of cytokines, which activate microglia and astrocytes and stimulate endothelial cells to promote entry of peripheral immune cells. Cytotoxic compounds that are released from these activated cells combine to produce neurodegeneration. The underlying mechanisms will be tested in vivo by the strategy successfully used in our ongoing experiments. The sequences of responses of cell-specific changes in markers of inflammation, vascular responses and oxidative stress will be established. Specific drug treatments and, where feasible, transgenic animals will be used to test whether each specific step is critical in the cascade leading to neurodegeneration. An understanding of these mechanisms will likely suggest new ways to overcome the consequences of the mild, chronic impairment of oxidative metabolism that accompanies numerous age-related neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014600-10
Application #
6703662
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Wise, Bradley C
Project Start
1992-06-01
Project End
2008-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
10
Fiscal Year
2004
Total Cost
$299,400
Indirect Cost
Name
Winifred Masterson Burke Med Research Institute
Department
Type
DUNS #
780676131
City
White Plains
State
NY
Country
United States
Zip Code
10605
Gibson, Gary E; Hirsch, Joseph A; Fonzetti, Pasquale et al. (2016) Vitamin B1 (thiamine) and dementia. Ann N Y Acad Sci 1367:21-30
Huang, Hsueh-Meei; Chen, Huan-Lian; Gibson, Gary E (2014) Interactions of endoplasmic reticulum and mitochondria Ca(2+) stores with capacitative calcium entry. Metab Brain Dis 29:1083-93
Bubber, P; Hartounian, V; Gibson, G E et al. (2011) Abnormalities in the tricarboxylic acid (TCA) cycle in the brains of schizophrenia patients. Eur Neuropsychopharmacol 21:254-60
Huang, Hsueh-Meei; Chen, Huan-Lian; Gibson, Gary E (2010) Thiamine and oxidants interact to modify cellular calcium stores. Neurochem Res 35:2107-16
Gibson, Gary E; Starkov, Anatoly; Blass, John P et al. (2010) Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases. Biochim Biophys Acta 1802:122-34
Karuppagounder, Saravanan S; Xu, Hui; Shi, Qingli et al. (2009) Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model. Neurobiol Aging 30:1587-600
Shi, Qingli; Risa, Øystein; Sonnewald, Ursula et al. (2009) Mild reduction in the activity of the alpha-ketoglutarate dehydrogenase complex elevates GABA shunt and glycolysis. J Neurochem 109 Suppl 1:214-21
Karuppagounder, Saravanan S; Pinto, John T; Xu, Hui et al. (2009) Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease. Neurochem Int 54:111-8
Gibson, Gary E; Karuppagounder, Saravanan S; Shi, Qingli (2008) Oxidant-induced changes in mitochondria and calcium dynamics in the pathophysiology of Alzheimer's disease. Ann N Y Acad Sci 1147:221-32
Karuppagounder, Saravanan S; Xu, Hui; Pechman, David et al. (2008) Translocation of amyloid precursor protein C-terminal fragment(s) to the nucleus precedes neuronal death due to thiamine deficiency-induced mild impairment of oxidative metabolism. Neurochem Res 33:1365-72

Showing the most recent 10 out of 56 publications