The goal of this project is to investigate the mechanisms through which RXRs (retinoid x nuclear receptor) promote amyloid clearance from the brain.
There is now persuasive evidence that sporadic, late-onset forms of AD arise from impaired clearance of Abeta from the brain. Moreover, the elevated risk associated with possession of an ApoE4 allele is correlated with a reduced capacity to remove Abeta from the brain. These findings are consistent with the ability of ApoE to facilitate the proteolytic degradation of Abeta, and ApoE4 is less efficient in doing so. These data argue that elevation of ApoE levels in the brain would enhance the physiological mechanisms that aid Abeta clearance. ApoE expression and subsequent lipidation is transcriptionally regulated through the coordinated actions of the nuclear receptors PPARg and LXR. These ligand-activated receptors form obligate heterodimers with RXRs to create a functional transcription factor. Preliminary data demonstrating the oral administration of the RXR-specific agonist, bexarotene, results in the rapid, ApoE-dependent clearance of soluble Abeta in the interstitial fluid within hours. Moreover, bexarotene treatment provokes the loss of more than 60 percent of amyloid plaques from aged APP/PS1 mice within 72 hours, coincident with the appearance of amyloid-laden, phagocytic microglia. This latter effect is postulated to arise from the ability of the nuclear receptors to stimulate the conversion of microglia into M2 or “alternative activation” states associated with suppression of inflammatory gene expression and induction of genes promoting phagocytosis.
Thus, the effects of the activation of RXRs on AD pathology arise from two distinct transcriptional programs that operate in different cell types. The genetic targets of RXR action in the brain are largely unknown. This application represents a collaboration between the laboratories of Drs. David Holtzman, Rudolph Tanzi and Gary Landreth that is focused on investigating the mechanisms through which RXRs promote amyloid clearance from the brain.