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Effect of liver x receptor target genes Apolipoprotein E and ATP-binding cassette transporter A1 on beta-amyloid dependent pathology in Alzheimer's disease model mice

Carter, Alexis (2017) Effect of liver x receptor target genes Apolipoprotein E and ATP-binding cassette transporter A1 on beta-amyloid dependent pathology in Alzheimer's disease model mice. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that overtime interferes with daily tasks. Late-onset Alzheimer’s disease (LOAD) is a multifactorial disease with a combination of genetic and environmental risk factors. The APOEε4 allele of Apolipoprotein E (APOE) is the major genetic risk factor for LOAD. However, APOEε3 patients still account for the majority of LOAD cases, suggesting additional genetic, environmental, and lifestyle factors as risk modifiers.
We examined the effect of high-fat diet (HFD) and liver x receptor (LXR) agonist T0901317 (T0) in representative mouse models of AD phenotype. LXRs regulate cholesterol and lipoprotein metabolism. ATP-binding cassette transporter A1 (ABCA1) and APOE are major LXR target genes involved in lipid and cholesterol generation and transport and are implicated in AD pathology. We determined that Abca1ko mice have cognitive deficits. Lack of ABCA1 impaired neurite morphology in the CA1 region of the hippocampus. We then examined the effect of HFD on memory deficits and microglia morphology in AD model mice expressing either mouse Apoe or human APOE isoforms. HFD exacerbated cognitive deficits in APP23 mice. Microglia morphology resembled activation state in HFD fed female APOE4 mice, suggesting differential response to diet. Lastly, we examined the effects of T0 on the phenotype and transcriptome of APP/E3 and APP/E4 Abca1 haplo-deficient mice, revealing the ability of T0 to ameliorate APOE4-driven pathological phenotype.
These findings suggest that disturbances in cholesterol metabolism may negatively impact AD-related patholoy, HFD exacerbates AD-related pathology, and that T0 treatment ameliorates APOE4-induced AD pathogenesis. These results could have clinical implications on lifestyle or dietary and pharmacological interventions for AD patients. The public health significance of this research supports efforts in developing primary prevention techniques, with the end goal of inhibiting or delaying disease onset, AD-related pathology, and promoting healthy brain aging. Targeting the LXR-ABCA1-APOE regulatory axis could be an effective therapy for individuals at risk of dementia and to treat AD patients regardless of APOE genotype. Further developing studies that better assess cholesterol metabolism genes in AD pathology are essential for modifying guidelines and therapies for those at risk of dementia.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Carter, Alexisalexisc@pitt.edualexisc
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSt. Croix, Claudettecls13@pitt.edu
Thesis AdvisorKoldamova, Radosvetaradak@pitt.edu
Committee MemberLefterov, Iliyailiyal@pitt.edu
Committee MemberDemirci, Yesim/ Ffyd1@pitt.edu
Committee MemberDefranco, Donalddod1@pitt.edu
Date: 24 February 2017
Date Type: Publication
Defense Date: 5 December 2016
Approval Date: 24 February 2017
Submission Date: 28 November 2016
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 133
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Alzheimer's disease, Apolipoprotein E, ATP-binding cassette transporter A1, High density lipoproteins, Novel Object Recognition
Date Deposited: 24 Feb 2017 19:15
Last Modified: 01 Jan 2020 06:15
URI: http://d-scholarship.pitt.edu/id/eprint/30421

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