Alzheimer's disease (AD) is the most prevalent form of age-associated dementia. Cholesterol dysregulation is linked with AD onset. Besides age, the most important risk factor associated with AD is the inheritance of the epsilon-4 allele of apolipoprotein E, a cholesterol transporter. In addition, while hypercholesterolemia has been shown to be an independent risk factor for AD, the nature of the cholesterol-AD link is still not clear. This gap in our understanding is partly due to a lack of knowledge about cholesterol metabolism in the central nervous system (CNS).
The low-density lipoprotein receptor (LDLR) is the main receptor of apoE and a central regulator of serum cholesterol levels. Therefore, we sought to characterize the potential participation of LDLR in AD pathogenesis and/or progression. Previous reports with similar aims came to contradictory conclusions. Such studies assessed potential changes in AD in the absence of LDLR by utilizing the LDLR-/- mouse model and crossing it to AD mouse models.
Initially we evaluated LDLR-/- mice as a suitable model to study AD. We found that LDLR-/- mice overexpressed a functional splice-variant of LDLR, LDLRDelta4. Moreover, its protein localized in similar regions as the LDLR did in control mice. Finally, we determined that LDLRDelta4 bound apoE, which underscores the impact of the isoform's function in the CNS.
We then focused on characterizing changes to LDLR in AD models. We found that APP overexpression in cells increased LDLR mRNA and protein. APP overexpression and Abeta treatment shifted LDLR localization. An AD mouse model showed increased LDLR in hippocampus. Conversely, LDLR levels were decreased in APP-/- mice. Finally, we found that microtubules were affected in cells overexpressing APP.
In conclusion, the data presented argue for the importance of LDLR-mediated regulation of cholesterol during AD progression. Also, LDLR may participate in the initial pathogenic insults leading to amyloid deposition, which make it a potential therapeutic target to treat AD. Finally, we propose that APP/Abeta overexpression disrupts microtubule formation; this alteration affects protein trafficking. One of the proteins affected is LDLR, the repercussions of which may ultimately result in cholesterol dysregulation.
| Identifer | oai:union.ndltd.org:USF/oai:scholarcommons.usf.edu:etd-2553 |
| Date | 30 December 2009 |
| Creators | Abisambra Socarras, Jose Francisco |
| Publisher | Scholar Commons |
| Source Sets | University of South Flordia |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Graduate Theses and Dissertations |
| Rights | default |
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