Project 5: PICALM, Oligomeric Abeta and Inflammation in Neurovascular Pathogenesis in AD In this renewal the emphasis will still be on how Abeta and inflammation affect cerebrovascular function, but will also take advantage of recent genome-wide association studies (GWAS) that have identified new AD risk genes that have been broadly linked to inflammation/endosomal processing. Because the blood brain barrier (BBB) is critically important for efficient transport of solutes in and out of the central nervous system (CNS), and phosphatidylinositol-binding clathrin assembly protein (PICALM) one of the genes identified with increased risk for AD is involved with initiating endocytosis/transcytosis of APP, ApoE and Abeta by endothelial cells, we have chosen to focus on how the PICALM risk variant affects endothelial function in the presence oligomeric Ap, angiotensin II, and inflammation (IL-1beta). Finally, because meta-analysis of AD risk loci has revealed interactions between PICALM and APOE genotypes, where PICALM conferred risk predominantiy in APOE e4-positive subjects, we propose to include APOE genotypes in our research strategy. Since PICALM knockout mice show deficits in erythroid maturation and transferrin internalization, we hypothesize that the PICALM risk variant represents either a deficit in endocytosis or an altered trafficking function where vesicle cargo is misrouted. We propose the following Specific Aims:
Aim 1 : To investigate the contribution of the PICALM AD risk variant on the level of parenchymal amyloid load, type-1 and type-2 cerebral amyloid angiopathy, Ap40 &42 levels, tau, and inflammation in the UCI ADRC autopsy cases.
Aim 2 : We will investigate how human iPSCs-derived ECs homozygous PICALM risk or non-risk alleles affect endocytic function and vesicular trafficking in endothelial cells (APOE genotypes 3/3, versus ?3/?4).
Aim 3 : We will test endocytosis and transcytosis of transferrin, LRP1, ApoE and TrkB receptors, as well as APP and Ap using an in vitro transwell model of the BBB. We will use iPSCs-derived ECs homozygous for PICALM risk or non-risk coding variants and astrocytes from Down syndrome (DS) and non-DS that express APOE ?3/?3 or ApoE ?3/?4.
Aim 4 : To test the role of PICALM in EC BBB function on Ap vascular pathology in vivo. We propose to develop a transgenic mouse model with reduced expression of PICALM in endothelial cells using the Cre-LoxP System. The conditional EC PICALM knock-out mice will be crossed with APP Tg mice that develop Type 2 CAA or Type 1 CAA and the effect of PICALM knockdown on CAA, as well as parenchymal Abeta will be assessed.

Public Health Relevance

The rationale for focusing on the cerebral vascular system in Project 5 is that the common co-occurrence of AD and vascular pathology mesh with epidemiologic data showing that many vascular risk factors are also risk factors for brain atrophy and dementia. The blood brain barrier (BBB) is critically important for efficient transport of solutes in and out of the central nervous system, and PICALM is involved with initiating endocytosis/transcytosis of APP, ApoE, clusterin and Abeta by endothelial cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG000538-34A1
Application #
8726538
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-03-31
Support Year
34
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Type
DUNS #
City
Irvine
State
CA
Country
United States
Zip Code
92697
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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