There is evidence that the complement (C), a major mediator of inflammatory responses may play an important role in Alzheimer's disease (AD) neuropathology. The proposed studies focus on brain experimental lesions to model select aspects of AD and aim at the understanding the role of C in mechanisms of hippocampal neuron death/survival and synaptic plasticity. In preliminary studies, we found that subsets of hippocampal pyramidal neurons in congenic mice genetically deficient of C component C5 (C5-) are more susceptible to glutamate neurotoxicity when compared to C5 sufficient (C5+) mice. We also found that the C5 derived anaphylatoxin C5a, diminished glutamate mediated neurotoxicity in hippocampal neuron cultures. We will attempt to further dissect the mechanisms which may underlie the neuroprotective role of the pro.inflammatory anaphylatoxin C5a. Specifically, we will attempt: (l.) characterize the role of C5a in hippocampal responses to experimental lesions using a C5a-receptor (C5aR) knockout mouse model, (2.) identify the actions of C5a on hippocampal neurons in intact adult brain and with experimental lesions, (3.) characterize the trophic /neuroprotective actions of hrC5a on hippocampal neuron in culture, (4.) characterize in C5-, C5+ and C5aR knockout mice altered glutamate receptors gene expression which we hypothesize might be under C5a control. These studies will clarify the role of C in brain and will lead to better understanding the mechanisms which may underlie the neuroprotective role of the anaphylatoxin C5a. They may lead to a better understanding of C mediated pathophysiology in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013799-03
Application #
2517048
Study Section
Pathology A Study Section (PTHA)
Project Start
1995-09-20
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
3
Fiscal Year
1997
Total Cost
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