Safety, Tolerability, and Changes in Amyloid β Concentrations After Administration of a γ-Secretase Inhibitor in Volunteers

Siemers, Eric; Skinner, Michael H.; Dean, Robert A.; Gonzales, Celedon; Satterwhite, Julie; Farlow, Martin R.; Ness, Daniel; May, Patrick C.

doi:10.1097/01.wnf.0000167360.27670.29

Cited by 213 publications

(159 citation statements)

References 42 publications

(39 reference statements)

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“…Because Aβ is generated when β-or γ-secretase cleaves APP, secretase-inhibiting drugs are being investigated and progress is expected. 30) Research of low molecular, such as cystamine, compounds that suppress Aβ aggregation is also advancing. 31,32) Phagocytosis of Aβ by microglia or its degradation by proteolytic enzymes such as neprilysin and insulin-degrading enzyme has been suggested as one means of promoting clearance.…”

Section: Discussionmentioning

confidence: 99%

Shuttling Protein Nucleolin Is a Microglia Receptor for Amyloid Beta Peptide 1-42

Ozawa

Nakamura

Koike

et al. 2013

Biological & Pharmaceutical Bulletin

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Amyloid-beta peptide 1-42 (Aβ42) plays a key role in the neurotoxicity found in Alzheimer's disease. Mononuclear phagocytes in the brain (microglia), can potentially clear Aβ via phagocytosis. Recently, the shuttling-protein nucleolin has been shown to possess scavenger receptor-activity. Here, we investigated whether this receptor interacts specifically with Aβ type 1-42 and mediates its phagocytosis by microglia. While monomeric and fibril Aβ42 were phagocytosed by mouse microglial EOC2 cells, amyloid β peptide 1-40 (Aβ40) was only weakly phagocytosed. Surface plasmon-resonance analysis revealed that nucleolin strongly associates with Aβ42, but only weakly associates with Aβ40. Immunofluorescence staining of antinucleolin antibody revealed that EOC2 cells and rat primary microglia express nucleolin on their cell surfaces. Further, pretreating EOC2 cells with anti-nucleolin antibody, but not immunoglobulin G (IgG), inhibited phagocytosis of monomeric Aβ42 by microglia. Additionally, nucleolin-transfected HEK293 cells phagocytosed monomeric and fibril Aβ42 but not monomeric and fibril Aβ40. Moreover, AGRO, a nucleolin-specific oligonucleotide aptamer, inhibited phagocytosis of monomeric and fibril Aβ42, but not monomeric and fibril Aβ40. These results indicate that nucleolin is a receptor that allows microglia to recognize monomeric and fibril Aβ42.

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Section: Discussionmentioning

confidence: 99%

Shuttling Protein Nucleolin Is a Microglia Receptor for Amyloid Beta Peptide 1-42

Ozawa

Nakamura

Koike

et al. 2013

Biological & Pharmaceutical Bulletin

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“…In addition, a low dose of LY-411575 in Tg2576 mice has been shown to elevate plasma A␤1-40 and A␤1-42 while having no effect upon CSF or brain A␤ (Lanz et al, 2004). A structurally related ␥-secretase inhibitor, LY-450139, has since been shown to elevate plasma A␤ levels in beagles and in human volunteers either at low doses that had no effect upon CSF A␤ or at higher doses that initially lowered plasma A␤ but later elevated plasma A␤ above baseline (Hyslop et al, 2004;Siemers et al, 2005).…”

mentioning

confidence: 99%

Concentration-Dependent Modulation of Amyloid-β in Vivo and in Vitro Using the γ-Secretase Inhibitor, LY-450139

Lanz

Karmilowicz²,

Wood³

et al. 2006

J Pharmacol Exp Ther

128

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LY-450139 is a ␥-secretase inhibitor shown to have efficacy in multiple cellular and animal models. Paradoxically, robust elevations of plasma amyloid-␤ (A␤) have been reported in dogs and humans after administration of subefficacious doses. The present study sought to further evaluate A␤ responses to LY-450139 in the guinea pig, a nontransgenic model that has an A␤ sequence identical to that of human. Male guinea pigs were treated with LY-450139 (0.2-60 mg/kg), and brain, cerebrospinal fluid, and plasma A␤ levels were characterized at 1, 3, 6, 9, and 14 h postdose. Low doses significantly elevated plasma A␤ levels at early time points, with return to baseline within hours. Higher doses inhibited A␤ levels in all compartments at early time points, but elevated plasma A␤ levels at later time points. To determine whether this phenomenon occurs under steadystate drug exposure, guinea pigs were implanted with subcutaneous minipumps delivering LY-450139 (0.3-30 mg/kg/day) for 5 days. Plasma A␤ was significantly inhibited at 10 -30 mg/kg/day, but significantly elevated at 1 mg/kg/day. To further understand the mechanism of A␤ elevation by LY-450139, H4 cells overexpressing the Swedish mutant of amyloid-precursor protein and a mouse embryonic stem cell-derived neuronal cell line were studied. In both cellular models, elevated levels of secreted A␤ were observed at subefficacious concentrations, whereas dose-responsive inhibition was observed at higher concentrations. These results suggest that LY-450139 modulates the ␥-secretase complex, eliciting A␤ lowering at high concentrations but A␤ elevation at low concentrations.The pathological accumulation of amyloid-␤ peptide into dense core plaques in the brains of Alzheimer's disease patients is the ultimate target of multiple disease-modifying drug discovery efforts. One strategy that has entered the clinic is the use of a ␥-secretase inhibitor to reduce central A␤ production. Preclinically, multiple ␥-secretase inhibitors have demonstrated central and peripheral A␤-lowering activity in transgenic mouse lines overexpressing human mutant amyloid precursor protein (Dovey et al., 2001;Cirrito et al., 2003;Lanz et al., 2003Lanz et al., , 2004Wong et al., 2004;, as well as nontransgenic species (Anderson et al., 2005;Best et al., 2006;El Mouedden et al., 2006). Whereas acute treatment of old, plaque-bearing mice should have little immediate impact on plaque load (insoluble A␤), these inhibitors have been shown to inhibit A␤ in CSF (Lanz et al., 2003;Barten et al., 2005) and interstitial fluid (Cirrito et al., 2003) similarly in both plaque-free and plaque-bearing mice. In addition, plasma A␤ has been shown to be reduced similarly by ␥-secretase inhibition in both young and old Tg2576 mice (Lanz et al., 2003;Barten et al., 2005). These findings indicate that despite the presence or absence of insoluble A␤ plaques, these compounds had similar potency in reducing soluble, secreted A␤ in young and old transgenic mice.The ability of plasma and CSF A␤ to track pharmacologic...

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“…Despite the problems, progress towards human therapy has been made. Human studies have been begun with γ-secretase inhibitors [67,68].…”

Section: Therapeutic Approaches That Decrease Aβ Synthesismentioning

confidence: 99%

Impact of amyloid imaging on drug development in Alzheimer's disease

Mathis

Lopresti

Klunk

2007

Nuclear Medicine and Biology

111

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Imaging agents capable of assessing amyloid-beta (Aβ) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect Aβ plaques in the brain, to help test the amyloid cascade hypothesis of AD, and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several Aβ imaging agents are currently underway. We reported the first PET studies of the carbon-11-labeled thioflavin-T derivative Pittsburgh Compound B ([ 11 C]PiB) in 2004, and this work has subsequently been extended to include a variety of subject groups including AD, mild cognitive impairment (MCI), and healthy controls. The ability to quantify regional Aβ plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of Aβ plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials.

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Safety, Tolerability, and Changes in Amyloid β Concentrations After Administration of a γ-Secretase Inhibitor in Volunteers

Cited by 213 publications

References 42 publications

Shuttling Protein Nucleolin Is a Microglia Receptor for Amyloid Beta Peptide 1-42

Shuttling Protein Nucleolin Is a Microglia Receptor for Amyloid Beta Peptide 1-42

Concentration-Dependent Modulation of Amyloid-β in Vivo and in Vitro Using the γ-Secretase Inhibitor, LY-450139

Impact of amyloid imaging on drug development in Alzheimer's disease

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