ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models

Tian

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

197

180

Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer's disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17-treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development.Alzheimer's | amyloid | imaging | fluorescence | curcumin

Section: Discussionmentioning

confidence: 99%

Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

Tian

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

197

180

“…3 Bexarotene (4-[1- (3,5,5,8,8-pentamethyltetralin-2-yl)-ethenyl]benzoic acid, Figure 1), an FDA-approved selective RXR agonist, 4 has recently been demonstrated to induce clearance of β-amyloid from the brains of murine AD models through activation of the APOE gene, which is the most indicative genetic risk factor for late-onset AD. 5 In vitro and in vivo studies also suggest that bexarotene is acting on RXRs, and not directly on β-amyloid or by compromising the blood−brain barrier. 6 A transgenic mouse model of AD (Tg2576) exhibited reversal of cognitive and behavioral degradation with the administration of bexarotene.…”

mentioning

confidence: 99%

Synthesis of [¹¹C]Bexarotene by Cu-Mediated [¹¹C]Carbon Dioxide Fixation and Preliminary PET Imaging

Rotstein

Hooker

Woo

et al. 2014

ACS Med. Chem. Lett.

Bexarotene (Targretin) is a retinoid X receptor (RXR) agonist that has applications for treatment of T cell lymphoma and proposed mechanisms of action in Alzheimer's disease that have been the subject of recent controversy. Carbon-11 labeled bexarotene ([ 11 Ccarbonyl]4- [1-(3,5,5,8,8-pentamethyltetralin-2-yl)ethenyl]benzoic acid) was synthesized using a Cu-mediated cross-coupling reaction employing an arylboronate precursor 1 and [ 11 C]carbon dioxide under atmospheric pressure in 15 ± 2% uncorrected radiochemical yield (n = 3), based on [ 11 C]CO 2 . Judicious choice of solvents, catalysts, and additives, as well as precursor concentration and purity of [ 11 C]CO 2 , enabled the preparation of this 11 C-labeled carboxylic acid. Formulated [ 11 C]bexarotene was isolated (>37 mCi) with >99% radiochemical purity in 32 min. Preliminary positron emission tomography−magnetic resonance imaging revealed rapid brain uptake in nonhuman primate in the first 75 s following intravenous administration of the radiotracer (specific activity >0.3 Ci/μmol at time of injection), followed by slow clearance (Δ = −43%) over 60 min. Modest uptake (SUV max = 0.8) was observed in whole brain and regions with high RXR expression. KEYWORDS: Bexarotene, targretin, positron emission tomography, carbon-11, carbon dioxide fixation, retinoid X receptor, Alzheimer's disease R etinoid X receptors (RXRs) function as key transcription factors inasmuch as they are the heterodimeric partners for most nuclear receptors, including retinoic acid receptors (RARs), peroxisome proliferator-activated receptors (PPARs), vitamin D receptor, and thyroid hormone receptor. 1 Retinoid X ligands (e.g., 9-cis retinoic acid, Figure 1) are small lipophilic hormones, which, when bound to a heterodimeric or a homodimeric (i.e., RXR-RXR fusion) receptor, cause it to bind a transcription complex on DNA and to promote expression of target genes. RXRs are found ubiquitously and differentially in mammalian cells, including in both glial and neuronal brain tissue. 2 Defective retinoid signaling and deficiency of apolipoprotein E (ApoE) are closely associated with Alzheimer's disease (AD). 3 Bexarotene (4-[1-(3,5,5,8,8-pentamethyltetralin-2-yl)ethenyl]benzoic acid, Figure 1), an FDA-approved selective RXR agonist, 4 has recently been demonstrated to induce clearance of β-amyloid from the brains of murine AD models through activation of the APOE gene, which is the most indicative genetic risk factor for late-onset AD. 5 In vitro and in vivo studies also suggest that bexarotene is acting on RXRs, and not directly on β-amyloid or by compromising the blood−brain barrier. 6 A transgenic mouse model of AD (Tg2576) exhibited reversal of cognitive and behavioral degradation with the administration of bexarotene. 5 These findings have proven to be controversial, however, as several laboratories have struggled to reproduce both the scope and magnitude of the in vivo results. 7−11 An additional caveat to these results is that the bexarotene dose used to achieve these effect...

“…Therefore, developing therapeutic strategies that aim to suppress Aβ-induced cytotoxicity has been the main focus of research [14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats

Chai

Duan

et al. 2014

Neurosci. Bull.

Amyloid β-peptide (Aβ) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer's disease (AD). Humanin (HN) is a secretory peptide that inhibits the neurotoxicity of Aβ. However, the mechanism(s) by which HN exerts its neuroprotection against Aβ-induced ADlike pathological changes and memory deficits are yet to be completely defined. In the present study, we provided evidence that treatment of rats with HN increases the number of dendritic branches and the density of dendritic spines, and upregulates pre-and post-synaptic protein levels; these effects lead to enhanced long-term potentiation and amelioration of the memory deficits induced by Aβ 1-42 . HN also attenuated Aβ 1-42 -induced tau hyperphosphorylation, apparently by inhibiting the phosphorylation of Tyr307 on the inhibitory protein phosphatase-2A (PP2A) catalytic subunit and thereby activating PP2A. HN also inhibited apoptosis and reduced the oxidative stress induced by Aβ 1-42 . These fi ndings provide novel mechanisms of action for the ability of HN to protect against Aβ 1-42 -induced AD-like pathological changes and memory defi cits.