The goal of this project is to determine the effects of bexarotene on both Abeta and ApoE metabolism in the presence of human Abeta and human ApoE isoforms (any of two or more functionally similar proteins that have a similar but different amino acid sequence) because it is relevant to potential effects of similar drugs in humans.
A large amount of data strongly suggests the aggregation and deposition of the Abeta peptide in the brain is the initiating event in the pathological cascade known as Alzheimer’s disease (AD). This event appears to initiate a series of events, including exacerbation of Tau-related pathology, direct damage to neurons and synapses and damage to blood vessels from cerebral amyloid angiopathy (CAA). ApoE is the strongest genetic risk factor for AD, and is an important component of amyloid plaques that plays a direct role in determining whether, when and how much Abeta deposits accumulate in the brain (for review, see (Kim et al., 2009a)). The laboratory of Gary Landreth has found that activation of the retinoid X receptor (RXR) pathway, by a drug called bexarotene, strongly alters the levels of several proteins linked to lipid metabolism in the brain, including ApoE, ABCA1 and others. His lab also has found that bexarotene has very strong effects in decreasing soluble Abeta levels over hours as well as clearing amyloid plaques over days.
This finding has important treatment implications for AD. The Landreth lab data shows the effects of bexarotene on Abeta require ApoE; however, the experiments were done in mice that express murine ApoE. While murine ApoE is homologous to human ApoE, it is not identical at the amino acid level and some properties are different. For example, in APP transgenic mice that develop Abeta deposition, murine ApoE is much more amyloidogenic than any of the human ApoE isoforms (Fagan et al., 2002; Holtzman et al., 2000; Holtzman et al., 1999). Thus, it is important to determine the effects on bexarotene on both Abeta and ApoE metabolism in the presence of human Abeta and human ApoE isoforms, as this is more relevant to potential effects of this or similar drugs in humans. In these experiments, they will utilize 5XFAD mice, which express human mutant APP that leads to Abeta deposition beginning at around 4 months of age. The 5X FAD mice express human ApoE3 and human ApoE4. They will assess the effects of bexarotene on interstitial fluid Abeta levels over hours as well as its effects on behavior and Abeta deposition and associated pathology over weeks and months.