Nuclear receptors as therapeutic targets for Alzheimer's disease

Case Western Reserve University School of Medicine, Department of Neurosciences, Alzheimer Research Laboratory, Cleveland, OH 44106, USA.
Expert Opinion on Therapeutic Targets (Impact Factor: 5.14). 07/2011; 15(9):1085-97. DOI: 10.1517/14728222.2011.594043
Source: PubMed


INTRODUCTION: Alzheimer's disease (AD) is characterized by the accumulation and extensive deposition of amyloid β (Aβ) in the parenchyma of the brain. This accumulation of amyloid is associated with perturbations in synaptic function, impairments in energy metabolism and induction of a chronic inflammatory response which acts to promote neuronal loss and cognitive impairment. AREAS COVERED: Currently, there are no drugs that target the underlying mechanisms of AD. Here, we propose a class of nuclear receptors as novel and promising new therapeutic targets for AD. This review summarizes the literature on nuclear receptors and their effects on AD-related pathophysiology. EXPERT OPINION: Nuclear receptors are attractive targets for the treatment of AD due to their ability to facilitate degradation of Aβ, affect microglial activation and suppress the inflammatory milieu of the brain. Liver X receptor agonists have proven difficult to move into clinical trials as long-term treatment results in hepatic steatosis. It is our view that PPAR-γ activation remains a promising avenue for the treatment for AD; however, the poor BBB permeability of the currently available agonists and the negative outcome of the Phase III clinical trials are likely to diminish interest in pursuing this target.

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Available from: Gary Landreth, Sep 02, 2014
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    • "Agonists of RXRs stimulate the conversion of microglial cells to an alternative state [32] and increase phagocytosis [22] [33]. Previous studies investigated this by measuring either an increase in microglial cell activation [31] or the internalization of A␤ in Iba+ microglial cells [15], without detecting any BEXAmediated modifications. "
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    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia characterized by synaptic dysfunction, memory loss, neuroinflammation, and neuronal cell death. Amyloid-β (Aβ), recognized as the main culprit of AD, aggregates and accumulates in the extracellular compartment as neuritic plaques, after deregulation of its production or clearance. Apolipoprotein E (ApoE) plays a major role in Aβ clearance and its expression is transcriptionally regulated by the liver X receptor and retinoid X receptors (RXRs) system. Bexarotene (BEXA), an RXR agonist, that increases ApoE expression and microglia phagocytosis and has been proposed as a promising therapy for AD, resolving both the amyloid pathology and memory loss. Despite the first compelling report, however, multiple failures have been documented, raising concern about whether BEXA could in fact become a novel disease-modifying strategy for AD. To help clarify this, we investigated the effect of BEXA in vivo at multiple levels in TASTPM transgenic mice. Seven-day oral administration of BEXA to these mice did not achieve any significant memory improvement, plaque reduction, or enhancement of microglial cell activation. No differences were found when specifically investigating the microglial phagocytic state in vivo. In addition, a brain structural analysis with magnetic resonance did not detect any BEXA-mediated change in the volume reduction of the main affected brain areas in our mice. These results suggest that BEXA has no beneficial effect on the multi-factorial pathologic phenotype of AD mice.
    Journal of Alzheimer's disease: JAD 03/2015; 46(2). DOI:10.3233/JAD-150029 · 4.15 Impact Factor
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    • "LXRα is involved in the control of lipid homeostasis and inflammation, while the activation of LXRα-related downstream targets has beneficial effects in pathologic conditions, such as atherosclerosis [46], inflammation [47], and AD [48]. However, long-term activation of LXRα may lead to adverse side effects, including hepatic steatosis [49]. Thus, it is rational that there exist mechanisms, which can efficiently regulate the activation and/or expression of LXRα. "
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    ABSTRACT: Alzheimer's disease (AD) has been postulated to involve defects in the clearance of amyloid-β (Aβ). Activation of liver X receptor α (LXRα) increases the expression of apolipoprotein E (ApoE) as well as cholesterol transporters ABCA1 and ABCG1, leading to augmented clearance of Aβ. We have previously shown that the C allele of rs7120118 in the NR1H3 gene encoding LXRα reduces the risk of AD. Here, we wanted to assess whether the rs7120118 variation affects the progression of AD and modulates the expression of NR1H3 and its downstream targets APOE, ABCA1 and ABCG1.We utilized tissue samples from the inferior temporal cortex of 87 subjects, which were subdivided according to Braak staging into mild, moderate and severe AD groups on the basis of AD-related neurofibrillary pathology. APOE ε4 allele increased soluble Aβ42 levels in the tissue samples in a dose-dependent manner, but did not affect the expression status of APOE. In contrast, the CC genotype of rs7120118 was underrepresented in the severe group, although this result did not reach statistical significance. Also, patients with the CC genotype of rs7120118 showed significantly decreased soluble Aβ42 levels as compared to the patients with TT genotype. Although the severity of AD did not affect NR1H3 expression, the mRNA levels of NR1H3 among the patients with CT genotype of rs7120118 were significantly increased as compared to the patients with TT genotype. These results suggest that genetic variation in NR1H3 modulates the expression of LXRα and the levels of soluble Aβ42.
    PLoS ONE 11/2013; 8(11):e80700. DOI:10.1371/journal.pone.0080700 · 3.23 Impact Factor
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    • "Indeed, the LXR agonists GW3965 and TO901317 were reported to increase APOE expression in astrocytes, enhance Aβ clearance and ameliorate the memory deficit in amyloid mouse model [66,67]. Similar to LXRs, PPARγ agonists such as pioglitazone and ciglitazone can also induce APOE expression and rescue the behavioral deficits in AD mouse model [39,68]. In addition, RXR activation by numerous compounds has shown to increase APOE level, likely through activation of RXR and PPAR signaling pathways [74,75]. "
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    ABSTRACT: Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by loss of memory and cognitive function. A key neuropathological event in AD is the accumulation of amyloid-beta (Abeta) peptide. The production and clearance of Abeta in the brain are regulated by a large group of genes. The expression levels of these genes must be fine-tuned in the brain to keep Abeta at a balanced amount under physiological condition. Misregulation of AD genes has been found to either increase AD risk or accelerate the disease progression. In recent years, important progress has been made in uncovering the regulatory elements and transcriptional factors that guide the expression of these genes. In this review, we describe the mechanisms of transcriptional regulation for the known AD genes and the misregualtion that leads to AD susceptibility.
    Molecular Brain 10/2013; 6(1):44. DOI:10.1186/1756-6606-6-44 · 4.90 Impact Factor
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