Project 4: Neuroprotection and neuroinflammation induced by the complement proteins and receptors In order to increase the successful identification of novel therapeutic targets for degenerative disorders commonly seen in the elderiy, the interrelations between new discoveries in genetics (GWAS identified risk association genes), cell biology (autophagy), immunology (inflammasomes) and neurobiology must be delineated using a combination of experimental approaches. One rapidly emerging area is the link between the immune system and cellular homeostasis in neurobiological systems, consistent with a role for the immune system components in normal and pathological brain function. The complement system is a powerful effector mechanism of the innate immune system that contributes to protection from infection and resolution of injury. Complement component deposition has been associated with Alzheimer's disease (AD), macular degeneration, Parkinson's disease and other age-related neurodegenerative disorders. While the activation of the complement cascade may be detrimental in these diseases, C l q , the initiator molecule of the classical complement pathway, has anti-inflammatory effects in the absence of the other components of the complement system. Unexpectedly, it has become apparent that in the brain C l q synthesis is induced in response to a variety of insults and injury initially in the absence of synthesis of other complement components. In addition, our lab made the novel observation that in vitro C l q improves neuronal survival under nutrient stressed conditions and suppresses amyloid beta-induced neuronal death suggesting that C l q may have a neuroprotective role. This novel neuroprotection triggered by C l q was associated with induction of expression of neuronal genes which if suppressed abrogated the C l q neuroprotective effects. Here we will collaborate with other members of the Program Project to identify the mechanisms of this C l q neuroprotection/survival, determine if this coordinates with a GWAS identified risk polymorphism in CRI, and create new animal models to elucidate the significance of this pathway in in vivo models of neurodegenerative diseases in aging populations. The molecular delineation of this novel pathway should uncover a number of potential therapeutic targets which have not been explored which can then be translated into innovative strategies (perhaps in combination with other therapeutic targets) in the clinic for the enhancement of neuron survival to improve the quality of life for individuals suffering from neurodegenerative or neurodevelopmental disorders.

Public Health Relevance

This project will identify key signaling pathways and molecular interactions that are required for a novel neuroprotection mechanism discovered in our laboratory and determine if this pathway improves neuronal survival in an animal model of Alzheimer's Disease (AD). In a complementary approach the biological basis of the AD risk association of a polymorphism in an immune regulatory protein, CRI, will be determined. These results will provide the first step in design of novel pharmacologic interventions for degenerative diseases in humans.

National Institute of Health (NIH)
Research Program Projects (P01)
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University of California Irvine
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Rice, Rachel A; Berchtold, Nicole C; Cotman, Carl W et al. (2014) Age-related downregulation of the CaV3.1 T-type calcium channel as a mediator of amyloid beta production. Neurobiol Aging 35:1002-11
Elmore, Monica R P; Najafi, Allison R; Koike, Maya A et al. (2014) Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82:380-97
Berchtold, Nicole C; Sabbagh, Marwan N; Beach, Thomas G et al. (2014) Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease. Neurobiol Aging 35:1961-72
Hatami, Asa; Albay 3rd, Ricardo; Monjazeb, Sanaz et al. (2014) Monoclonal antibodies against A?42 fibrils distinguish multiple aggregation state polymorphisms in vitro and in Alzheimer disease brain. J Biol Chem 289:32131-43
Smith, Erica D; Prieto, G Aleph; Tong, Liqi et al. (2014) Rapamycin and interleukin-1? impair brain-derived neurotrophic factor-dependent neuron survival by modulating autophagy. J Biol Chem 289:20615-29
Pensalfini, Anna; Albay 3rd, Ricardo; Rasool, Suhail et al. (2014) Intracellular amyloid and the neuronal origin of Alzheimer neuritic plaques. Neurobiol Dis 71:53-61
Passos, Giselle F; Medeiros, Rodrigo; Cheng, David et al. (2013) The bradykinin B1 receptor regulates A? deposition and neuroinflammation in Tg-SwDI mice. Am J Pathol 182:1740-9
Medeiros, Rodrigo; LaFerla, Frank M (2013) Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol 239:133-8
Benoit, Marie E; Hernandez, Michael X; Dinh, Minhan L et al. (2013) C1q-induced LRP1B and GPR6 proteins expressed early in Alzheimer disease mouse models, are essential for the C1q-mediated protection against amyloid-* neurotoxicity. J Biol Chem 288:654-65
Fonseca, Maria I; McGuire, Susan O; Counts, Scott E et al. (2013) Complement activation fragment C5a receptors, CD88 and C5L2, are associated with neurofibrillary pathology. J Neuroinflammation 10:25

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