There is evidence that the complement system, a major component of inflammatory responses, may play an important role in neurodegenerative conditions such as Alzheimer's disease (AD). The proposed studies focus on elucidating the role of the anaphylatoxin CSa in mechanisms of neurodegeneration. During the past grant period, the investigators have demonstrated that mice genetically deficient in the complement component CS are more susceptible to excitotoxic neurodegeneration, and that the C5-derived anaphylatoxin C5a may protect against glutamate and p-amyloid (Ap) mediated neurotoxicity in part through inhibition of caspase 3, an executioner of apoptotic dell death. This neuroprotective role of CSa complicates current theories that complement proteins may be involved in the pathogenesis of AD neurodegeneration. For the next grant period, they propose to extend this novel finding with a focus on CSa mediated signal transduction mechanisms involved in neuroprotection. Ongoing studies suggest that human recombinant (hr) CSa may neuroprotect against glutamate and Abeta 1-42 mediated neurotoxicity through mechanisms that involve inhibition of caspase and activation of mitogen activated protein (MAP)- kinase pathways. Further characterization of the complex role of complement proteins in neurodegeneration is essential especially in view of the possibility that the complement system represents a target for therapeutic interventions in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013799-07
Application #
6532487
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Snyder, Stephen D
Project Start
1995-09-20
Project End
2005-07-31
Budget Start
2002-08-01
Budget End
2005-07-31
Support Year
7
Fiscal Year
2002
Total Cost
$296,625
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Mukherjee, Piali; Thomas, Sunil; Pasinetti, Giulio Maria (2008) Complement anaphylatoxin C5a neuroprotects through regulation of glutamate receptor subunit 2 in vitro and in vivo. J Neuroinflammation 5:5
Xiang, Zhongmin; Thomas, Sunil; Pasinetti, Giulio (2007) Increased neuronal injury in transgenic mice with neuronal overexpression of human cyclooxygenase-2 is reversed by hypothermia and rofecoxib treatment. Curr Neurovasc Res 4:274-9
Zhao, Zhong; Xiang, Zhongmin; Haroutunian, Vahram et al. (2007) Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer's disease. Neurobiol Aging 28:824-30
Qin, W; Peng, Y; Ksiezak-Reding, H et al. (2006) Inhibition of cyclooxygenase as potential novel therapeutic strategy in N141I presenilin-2 familial Alzheimer's disease. Mol Psychiatry 11:172-81
Zhao, Zhong; Ho, Lap; Wang, Jun et al. (2005) Connective tissue growth factor (CTGF) expression in the brain is a downstream effector of insulin resistance- associated promotion of Alzheimer's disease beta-amyloid neuropathology. FASEB J 19:2081-2
Qin, Weiping; Ho, Lap; Pompl, Patrick N et al. (2003) Cyclooxygenase (COX)-2 and COX-1 potentiate beta-amyloid peptide generation through mechanisms that involve gamma-secretase activity. J Biol Chem 278:50970-7
Xiang, Zhongmin; Ho, Lap; Yemul, Shrishailam et al. (2002) Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology. Gene Expr 10:271-8
Xiang, Zhongmin; Ho, Lap; Valdellon, Jennifer et al. (2002) Cyclooxygenase (COX)-2 and cell cycle activity in a transgenic mouse model of Alzheimer's disease neuropathology. Neurobiol Aging 23:327-34
Ho, L; Guo, Y; Spielman, L et al. (2001) Altered expression of a-type but not b-type synapsin isoform in the brain of patients at high risk for Alzheimer's disease assessed by DNA microarray technique. Neurosci Lett 298:191-4
Mukherjee, P; Pasinetti, G M (2001) Complement anaphylatoxin C5a neuroprotects through mitogen-activated protein kinase-dependent inhibition of caspase 3. J Neurochem 77:43-9

Showing the most recent 10 out of 26 publications