Project 3: Role of Inflammation on Induction of Tau Pathology in the Brains of Transgenic IVIice Alzheimer disease (AD) impairs memory and causes cognitive and psychiatric deficits. The number of people with AD will quadruple to 115 million worldwide by 2050, with cumiulative costs of care in the absence of disease-modifying treatments exceeding $204rillion over the next 40 years alone in the USA. Should this expectation come to fruition, it will pose an unprecedented medical, social, and economic burden on our society. One of the most fundamental and unresolved questions in the field centers on elucidating the role that inflammation plays in disease progression, and in particular, how the cerebral buildup of p-amyloid (Ap) promotes inflammation and the development of hyperphosphorylated tau. Notably, our studies identified inflammation as an early and critical step that links Ap to tau pathology and cognitive decline. Supporting GWAS-derived evidence further reinforces the importance of inflammation, as single nucleotide polymorphisms in many immune-related genes significantly increase the probability of developing AD. Although inflammation is critical to disease progression, a detailed molecular analysis of specific mechanisms of the inflammatory response is greatly needed. Among numerous inflammatory pathways associated with AD, interleukin-ip (IL-ip) plays a critical pathogenic role. We hypothesize that AQ>alters intracellular protein clearance and trafficking, exacerbating IL-ip-mediated inflammation, eliciting tau pathology and synaptic and cognitive deficits. Our goal is to elucidate the impact of Ap on IL-ip signaling with emphasis on fiie relevance of protein clearance for IL-ip synthesis and protein trafficking for IL-1 receptor 1 (IL-1 Rl) levels. We developed several new and exciting transgenic models and viral approaches that add significantly to the field and enable us to dissect the molecular pathways by which Ap, IL-ip and tau interact and the mechanisms by which they adversely impact cognition during different stages of the disease process. Because a better understanding of these pathways is critical not only for academic reasons but also for helping to identify novel drug targets, the translational impact of this work is quite significant.

Public Health Relevance

Inflammation plays both a protective and damaging role in Alzheimer disease (AD), so to identify a long lasting and effective treatment, it is important that we better understand its underlying processes. Our studies implicate a critical cytokine called interleukin-ip (IL-1P) as a factor that accelerates AD pathology. Here we propose to study the molecular mechanisms by which this cytokine alters basic cell biological functions and how these changes affect AD pathogenesis.

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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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