| Cellular and Molecular Neurosciences Section |
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| Neuroprotective Signal Transduction |
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| One excellent example of a neuroprotective signal transduction pathway is that activated by the injury responsive cytokine tumor necrosis factor (TNF). TNF activates receptors linked through a series of adapter proteins to activation of the transcription factor NF-kB. NF-kB consists of the transcription factor dimer (p50 and p65) and an associated inhibitory subunit called IkB. Activation of NF-kB in response to TNF or other stimuli leads to increased expression of genes encoding cytoprotective proteins including manganese SOD, Bcl-2, calcium binding proteins and inhibitor of apoptosis proteins. It should be noted that many stimuli for cell death, including elevated calcium levels and, in some cases, activation of TNF receptors are also stimuli for activation of the anti-apoptotic transcription factor NF-kB. Thus, the relative intensity of activation of death and life signals may determine the ultimate fate in neurons and whether, during the aging process, pathological neuronal degeneration occurs. |
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| Considerable work performed at the LNS indicates that dietary restriction (a decrease in calorie intake) can have tremendous benefits for the aging brain. Work in the Cellular and Molecular Neuroscience Unit has shown that dietary restriction activates neuroprotective signaling pathways in neurons that involve increased expression of stress proteins such as Hsp70, as well as neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF). Apparently, dietary restriction imposes a mild stress on neurons and the neurons respond by increasing their ability to cope with further stresses. The increased resistance of neurons in the brains of animals maintained on dietary restriction suggests that dietary restriction in humans may guard against age-related neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and stroke. In support of this hypothesis are studies of LNS investigators who are examining the impact of dietary restriction on brain aging in monkeys. In addition, epidemiological data suggest that reduced calorie intake is associated with decreased risk for Alzheimer's and Parkinson's diseases. |
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| Roles for NF-kB in modulating neuronal and microlia functions and injury responses (see J. Neurochem. 74:443-456 (2000) for details). |
