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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG000538-38
Application #
9472877
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
38
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Type
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
Sosna, Justyna; Philipp, Stephan; Albay 3rd, Ricardo et al. (2018) Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease. Mol Neurodegener 13:11
Tong, Liqi; Prieto, G Aleph; Cotman, Carl W (2018) IL-1? suppresses cLTP-induced surface expression of GluA1 and actin polymerization via ceramide-mediated Src activation. J Neuroinflammation 15:127
Hainsworth, A H; Lee, S; Foot, P et al. (2018) Super-resolution imaging of subcortical white matter using stochastic optical reconstruction microscopy (STORM) and super-resolution optical fluctuation imaging (SOFI). Neuropathol Appl Neurobiol 44:417-426
Krotee, Pascal; Griner, Sarah L; Sawaya, Michael R et al. (2018) Common fibrillar spines of amyloid-? and human islet amyloid polypeptide revealed by microelectron diffraction and structure-based inhibitors. J Biol Chem 293:2888-2902
Prieto, G Aleph; Tong, Liqi; Smith, Erica D et al. (2018) TNF? and IL-1? but not IL-18 Suppresses Hippocampal Long-Term Potentiation Directly at the Synapse. Neurochem Res :
Carlos, Anthony J; Tong, Liqi; Prieto, G Aleph et al. (2017) IL-1? impairs retrograde flow of BDNF signaling by attenuating endosome trafficking. J Neuroinflammation 14:29
Fonseca, Maria I; Chu, Shu-Hui; Hernandez, Michael X et al. (2017) Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain. J Neuroinflammation 14:48
Abud, Edsel M; Ramirez, Ricardo N; Martinez, Eric S et al. (2017) iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases. Neuron 94:278-293.e9
Jun, Gyungah R; Chung, Jaeyoon; Mez, Jesse et al. (2017) Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimers Dement 13:727-738
Gonzalez, Bianca; Abud, Edsel M; Abud, Abigail M et al. (2017) Tau Spread, Apolipoprotein E, Inflammation, and More: Rapidly Evolving Basic Science in Alzheimer Disease. Neurol Clin 35:175-190

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