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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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University of California Irvine
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Spangenberg, Elizabeth E; Lee, Rafael J; Najafi, Allison R et al. (2016) Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. Brain 139:1265-81
Passos, Giselle F; Kilday, Kelley; Gillen, Daniel L et al. (2016) Experimental hypertension increases spontaneous intracerebral hemorrhages in a mouse model of cerebral amyloidosis. J Cereb Blood Flow Metab 36:399-404
Hatami, Asa; Monjazeb, Sanaz; Glabe, Charles (2016) The Anti-Amyloid-β Monoclonal Antibody 4G8 Recognizes a Generic Sequence-Independent Epitope Associated with α-Synuclein and Islet Amyloid Polypeptide Amyloid Fibrils. J Alzheimers Dis 50:517-25
Abbasi, Asghar; de Paula Vieira, Rodolfo; Bischof, Felix et al. (2016) Sex-specific variation in signaling pathways and gene expression patterns in human leukocytes in response to endotoxin and exercise. J Neuroinflammation 13:289
Acharya, Munjal M; Green, Kim N; Allen, Barrett D et al. (2016) Elimination of microglia improves cognitive function following cranial irradiation. Sci Rep 6:31545
Marsh, Samuel E; Abud, Edsel M; Lakatos, Anita et al. (2016) The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function. Proc Natl Acad Sci U S A 113:E1316-25
Linnartz-Gerlach, Bettina; Schuy, Christine; Shahraz, Anahita et al. (2016) Sialylation of neurites inhibits complement-mediated macrophage removal in a human macrophage-neuron Co-Culture System. Glia 64:35-47
Zhang, Liang; Trushin, Sergey; Christensen, Trace A et al. (2016) Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease. Sci Rep 6:18725
Snigdha, Shikha; Prieto, G Aleph; Petrosyan, Arpine et al. (2016) H3K9me3 Inhibition Improves Memory, Promotes Spine Formation, and Increases BDNF Levels in the Aged Hippocampus. J Neurosci 36:3611-22
Fonseca, Maria I; Chu, Shuhui; Pierce, Aimee L et al. (2016) Analysis of the Putative Role of CR1 in Alzheimer's Disease: Genetic Association, Expression and Function. PLoS One 11:e0149792

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