We have identified several growth factors and cytokines that can protect neurons against dysfunction and death in experimental models of Alzheimers disease, Parkinsons disease and stroke. These trophic factors activate signaling pathways that stimulate the expression of genes whose encoded proteins increase resistance of neurons to oxidative and metabolic stress. Neuroprotective Actions of BDNF. We have found that brain-derived neurotrophic factor (BDNF) is a key mediator of the neuroprotective effects of dietary restriction in animal models of Parkinsons and Huntingtons diseases. In other studies we have found that caloric restriction reduces damage to dopaminergic neurons and improves functional outcome in a non-human primate model of Parkinsons disease. The beneficial effect of CR is associated with increased amounts of BDNF and glial cell line-derived neurotrophic factor (GDNF), a growth factor which is now in early clinical trials in patients with Parkinsons disease. In related studies we have found that the antidepressant paroxetine can suppress neuronal degeneration and improve motor function and survival in a mouse model of Hungtingtons disease by a mechanism involving increased production of BDNF. In addition, we have identified GLP-1 (glucagon-like peptide 1) as a neuroprotective neuropeptide with the potential to ameliorate neuronal dysfunction and degeneration in some neurodegenerative conditions. More recently, we have demonstrated a neuroprotective role for the mitochondrial uncoupling protein UCP4, which acts by reducing levels of oxidative stress. UCP4 expression increases in response to dietary restriction and BDNF treatment, suggesting a role for UCP4 in the neuroprotective effects of dietary restriction and neurotrophic factors. In preclinical studies we have developed novel analogs of uric acid and histidine as neuroprotective agents in a mouse model of stroke. We have also shown that intravenous immunoglobulin and gamma-secretase inhibitors improve outcome following a stroke in mice, by a mechanism involving inhibition of the complement cascade. In addition, we have developed high throughput screens to identify chemicals that activate adaptive cellular stress response pathways, with several novel neuroprotective agents emerging from these screens. Moreover, we have demonstrated the ability of exendin-4, a GLP-1 analog used to treat diabetes, to ameliorate neurological deficits in animal models of stroke, Huntington's disease and Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000314-08
Application #
7732198
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2008
Total Cost
$1,150,803
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Schwartz, Catherine M; Tavakoli, Tahereh; Jamias, Charmaine et al. (2012) Stromal factors SDF1*, sFRP1, and VEGFD induce dopaminergic neuron differentiation of human pluripotent stem cells. J Neurosci Res 90:1367-81
Gleichmann, Marc; Zhang, Yongqing; Wood 3rd, William H et al. (2012) Molecular changes in brain aging and Alzheimer's disease are mirrored in experimentally silenced cortical neuron networks. Neurobiol Aging 33:205.e1-18
Widiapradja, Alexander; Vegh, Viktor; Lok, Ker Zhing et al. (2012) Intravenous immunoglobulin protects neurons against amyloid beta-peptide toxicity and ischemic stroke by attenuating multiple cell death pathways. J Neurochem 122:321-32
Mattson, Mark P (2011) A lifetime of dedication to the old in his Kentucky home. Neuromolecular Med 13:6-10
Yoon, Jeong Seon; Lee, Jong-Hwan; Son, Tae Gen et al. (2011) Pregabalin suppresses calcium-mediated proteolysis and improves stroke outcome. Neurobiol Dis 41:624-9
Romberg, Carola; Mattson, Mark P; Mughal, Mohamed R et al. (2011) Impaired attention in the 3xTgAD mouse model of Alzheimer's disease: rescue by donepezil (Aricept). J Neurosci 31:3500-7
Gleichmann, Marc; Mattson, Mark P (2010) Alzheimer's disease and neuronal network activity. Neuromolecular Med 12:44-7
Conant, K; Wang, Y; Szklarczyk, A et al. (2010) Matrix metalloproteinase-dependent shedding of intercellular adhesion molecule-5 occurs with long-term potentiation. Neuroscience 166:508-21
Jo, Dong-Gyu; Arumugam, Thiruma V; Woo, Ha-Na et al. (2010) Evidence that gamma-secretase mediates oxidative stress-induced beta-secretase expression in Alzheimer's disease. Neurobiol Aging 31:917-25
Hutchison, Emmette R; Okun, Eitan; Mattson, Mark P (2009) The therapeutic potential of microRNAs in nervous system damage, degeneration, and repair. Neuromolecular Med 11:153-61

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