Sporadic Alzheimer's disease (AD) is a late-onset dementia of unknown etiology, characterized by the presence of amyloid b (A?) containing senile plaques, neurofibrillary tangles, and cognitive decline. Importantly, the inheritance of Apolipoprotein (APOE) allele is the only established risk factor for sporadic late onset AD. However, the mechanism underlying this association remains elusive. ATP binding cassette transporter A1 (ABCA1) regulates cholesterol efflux from cells to cholesterol acceptors, primarily poorly lipidated apolipoprotein A-I (APOA-I) and APOE thus generating nascent high density lipoprotein (HDL). Disruption of Abca1 in APP expressing mice increased plaque levels in brain parenchyma and cerebral amyloid angiopathy. Remarkably this was accompanied by abnormal HDL-like particle structure in the CSF and decreased levels of APOA-I and APOE. Thus, processes that regulate APOE expression and lipidation could affect its ability to influence brain homeostasis. In support of this hypothesis the lower level of APOE in carriers is associated with increased pathology and AD risk. Furthermore, stimulation of APOE expression and lipidation with LXR and RXR agonists is associated with reduced pathology and improved cognition in AD mouse models. The central hypothesis is that Abca1 affects formation/deposition and clearance, through lipidation of ApoE and formation of HDL, therefore therapeutic approaches which affect the levels of Abca1 and ApoE can be used to treat the pathology. To prove the hypothesis we use viral vectors to overexpress apolipoproteins and multiphoton microscopy to assess in vivo the effects on A pathology and neuronal abnormalities in APP transgenic mice. Furthermore, we will characterize the effects of a clinically significant mutation of ABCA1 on APP mouse model phenotype. Lastly, we will examine how changes in peripheral and central expression of Abca1 affect lipid profiles and amyloid levels. The completion of this application will have a significant impact on our understanding of how different APOE alleles and a clinical relevant mutation of ABCA1 effects amyloid pathology. The design will allow for much more insight into a possible mechanism by which APOE affects AD progression. Furthermore, the application will further our understanding of the importance of central and peripheral ABCA1 in brain lipid profiles and amyloid levels, allowing for improved treatment targets. TRAINING IN THE RESPONSIBLE CONDUCT OF RESEARCH: Acceptable. The candidate has successfully completed training in the past and proposes additional focused training to supplement this background. The procedures for protection from research risks are satisfactory. Women and minorities are appropriately included in the research.

Public Health Relevance

The completion of this application will have a significant impact on our understanding of how overexpression of different APOE alleles affects the progression of amyloid pathology. Furthermore, the application will further our understanding of the importance of central and peripheral ABCA1 in the formation of HDL, determination of amyloid levels and cognitive decline, allowing for improved AD treatment targets. Lastly, these studies will help illuminate which genetic factors contribute to the susceptibility of AD and how carriers of different APOE alleles may respond to treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AG044490-03
Application #
9041470
Study Section
Neuroscience of Aging Review Committee (NIA)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Public Health & Prev Medicine
Type
Graduate Schools
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Castranio, Emilie L; Wolfe, Cody M; Nam, Kyong Nyon et al. (2018) ABCA1 haplodeficiency affects the brain transcriptome following traumatic brain injury in mice expressing human APOE isoforms. Acta Neuropathol Commun 6:69
Nam, Kyong Nyon; Wolfe, Cody M; Fitz, Nicholas F et al. (2018) Integrated approach reveals diet, APOE genotype and sex affect immune response in APP mice. Biochim Biophys Acta Mol Basis Dis 1864:152-161
Nam, Kyong Nyon; Mounier, Anais; Wolfe, Cody M et al. (2017) Effect of high fat diet on phenotype, brain transcriptome and lipidome in Alzheimer's model mice. Sci Rep 7:4307
Castranio, Emilie L; Mounier, Anais; Wolfe, Cody M et al. (2017) Gene co-expression networks identify Trem2 and Tyrobp as major hubs in human APOE expressing mice following traumatic brain injury. Neurobiol Dis 105:1-14
Fitz, Nicholas F; Carter, Alexis Y; Tapias, Victor et al. (2017) ABCA1 Deficiency Affects Basal Cognitive Deficits and Dendritic Density in Mice. J Alzheimers Dis 56:1075-1085
Carter, Alexis Y; Letronne, Florent; Fitz, Nicholas F et al. (2017) Liver X receptor agonist treatment significantly affects phenotype and transcriptome of APOE3 and APOE4 Abca1 haplo-deficient mice. PLoS One 12:e0172161
Sweet, Robert A; MacDonald, Matthew L; Kirkwood, Caitlin M et al. (2016) Apolipoprotein E*4 (APOE*4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease. Mol Cell Proteomics 15:2252-62
Nam, Kyong Nyon; Mounier, Anais; Fitz, Nicholas F et al. (2016) RXR controlled regulatory networks identified in mouse brain counteract deleterious effects of A? oligomers. Sci Rep 6:24048
Mounier, Anais; Georgiev, Danko; Nam, Kyong Nyon et al. (2015) Bexarotene-Activated Retinoid X Receptors Regulate Neuronal Differentiation and Dendritic Complexity. J Neurosci 35:11862-76
Fitz, Nicholas F; Tapias, Victor; Cronican, Andrea A et al. (2015) Opposing effects of Apoe/Apoa1 double deletion on amyloid-? pathology and cognitive performance in APP mice. Brain 138:3699-715

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