Project# 5: Oligomeric AB and Inflammation in Neurovascular Pathogenesis in AD In Alzheimer disease (AD) beta-amyloid (AB) deposition in the cerebrovasculature is common and there is increasing recognition that dysfunction in the BBB plays a critical role in many neurodegenerative diseases, including AD. The focus of this project is on the hypothesis that oligomer forms of AB activate CD-14-toll-like receptor 4 on the endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in the BBB. The resulting inflammatory response contributes to the deposition of fibrillar AB and induces a cerebrovascular inflammatory cascade that encompasses adjacent perivascular macrophages and astrocytes. The resulting chronic expression of proinflammatory cytokines, increases inflammatory cell adhesion molecules on endothelial cells, and attenuates trophic factor receptor-mediated signaling in the neurovascular unit. Moreover, because of the chronic exposure to AB oligomers and the subsequent deposition of fibrillar AB in vascular elements, these cells remain in a """"""""primed state"""""""" ready to be further activated. A secondary hypothesis is that chronic systemic inflammation exacerbates the inflammatory state of the cerebrovascular system. The role of oligomeric forms of AB in inflammation and degeneration in the cerebrovasculature remains largely unknown due to the lack of suitable animal models to investigate the pathological lesions associated with vascular deposition of AB. We will utilize APP2576 and Tg-SwDI mice because collectively they develop the broad spectrum of cerebrovascular pathology that are found in AD.
Aim 1 : Do oligomeric forms of AB correlate with the onset of inflammation in the cerebrovasculature in AD, Down Syndrome (DS), and APP/Tg mice? Aim 2: Do oligomeric forms of AB activate the CD14-TLR4 receptor complex? Do oligomeric forms of AB activate ECs and VSMCs? Do oligomeric forms of AB inhibit growth factor signaling in ECs and VSMCs? Aim 3: Does chronic systemic inflammation exacerbate cerebrovascular deposition of oligomeric AB and increase cerebrovascular inflammation? Aim 4: Therapeutic Strategies: Can anti-inflammatory approaches attenuate the inflammatory-induced adverse events in the cerebrovasculature in APP/Tg mice? Can transfected mesenchymal stem cells (MSCs) expressing a single chain anti-AB antibody attenuate AB oligomer-mediated cerebrovascular inflammation and degeneration?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG000538-33
Application #
8376749
Study Section
Special Emphasis Panel (ZAG1-ZIJ-3)
Project Start
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
33
Fiscal Year
2012
Total Cost
$256,418
Indirect Cost
$85,940
Name
University of California Irvine
Department
Type
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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 :
Prieto, G Aleph; Cotman, Carl W (2017) On the road towards the global analysis of human synapses. Neural Regen Res 12:1586-1589
Chen, E Y; Chu, S; Gov, L et al. (2017) CD200 modulates macrophage cytokine secretion and phagocytosis in response to poly(lactic co-glycolic acid) microparticles and films. J Mater Chem B 5:1574-1584
Snigdha, Shikha; Yassa, Michael A; deRivera, Christina et al. (2017) Pattern separation and goal-directed behavior in the aged canine. Learn Mem 24:123-131
Hernandez, Michael X; Namiranian, Pouya; Nguyen, Eric et al. (2017) C5a Increases the Injury to Primary Neurons Elicited by Fibrillar Amyloid Beta. ASN Neuro 9:1759091416687871
Hatami, Asa; Monjazeb, Sanaz; Milton, Saskia et al. (2017) Familial Alzheimer's Disease Mutations within the Amyloid Precursor Protein Alter the Aggregation and Conformation of the Amyloid-? Peptide. J Biol Chem 292:3172-3185

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