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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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University of California Irvine
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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 :
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
Love, Julia E; Day, Ryan J; Gause, Justin W et al. (2017) Nuclear uptake of an amino-terminal fragment of apolipoprotein E4 promotes cell death and localizes within microglia of the Alzheimer's disease brain. Int J Physiol Pathophysiol Pharmacol 9:40-57
Marsh, Samuel E; Yeung, Stephen T; Torres, Maria et al. (2017) HuCNS-SC Human NSCs Fail to Differentiate, Form Ectopic Clusters, and Provide No Cognitive Benefits in a Transgenic Model of Alzheimer's Disease. Stem Cell Reports 8:235-248
Krotee, Pascal; Rodriguez, Jose A; Sawaya, Michael R et al. (2017) Atomic structures of fibrillar segments of hIAPP suggest tightly mated ?-sheets are important for cytotoxicity. Elife 6:

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