Soluble Amyloid-beta Aggregates from Human Alzheimer’s Disease Brains

Esparza, Thomas J.; Wildburger, Norelle C.; Jiang, Hao; Gangolli, Mihika; Cairns, Nigel J.; Bateman, Randall J.; Brody, David L.

doi:10.1038/srep38187

Cited by 119 publications

(98 citation statements)

References 61 publications

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“…Rather, nonfibrillary soluble Ab oligomers appear to correlate with the development of the disease and to induce tau pathology (Lambert et al, 1998;Selkoe, 2008;Shankar et al, 2008;Ittner and Götz, 2011). These oligomers contain truncated and modified forms of Ab at a significant extent, as recently shown by Esparza et al (2016) and discussed at Alzforum (http:// www.alzforum.org/print-series/620566).…”

Section: Introductionmentioning

confidence: 85%

Glutaminyl Cyclase Inhibitor PQ912 Improves Cognition in Mouse Models of Alzheimer’s Disease—Studies on Relation to Effective Target Occupancy

Hoffmann

Meyer

Heiser

et al. 2017

J Pharmacol Exp Ther

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Numerous studies suggest that the majority of amyloid- (A) peptides deposited in Alzheimer's disease (AD) are truncated and post-translationally modified at the N terminus. Among these modified species, pyroglutamyl-A (pE-A, including N3pE-A40/42 and N11pE-A40/42) has been identified as particularly neurotoxic. The N-terminal modification renders the peptide hydrophobic, accelerates formation of oligomers, and reduces degradation by peptidases, leading ultimately to the accumulation of the peptide and progression of AD. It has been shown that the formation of pyroglutamyl residues is catalyzed by glutaminyl cyclase (QC). Here, we present data about the pharmacological in vitro and in vivo efficacy of the QC inhibitor (S)-1-(1H-benzo[d]imidazol-5-yl)-5-(4-propoxyphenyl)imidazolidin-2-one (PQ912), the first-in-class compound that is in clinical development. PQ912 inhibits human, rat, and mouse QC activity, with K values ranging between 20 and 65 nM. Chronic oral treatment of hAPPxhQC double-transgenic mice with approximately 200 mg/kg/day via chow shows a significant reduction of pE-A levels and concomitant improvement of spatial learning in a Morris water maze test paradigm. This dose results in a brain and cerebrospinal fluid concentration of PQ912 which relates to a QC target occupancy of about 60%. Thus, we conclude that >50% inhibition of QC activity in the brain leads to robust treatment effects. Secondary pharmacology experiments in mice indicate a fairly large potency difference for A cyclization compared with cyclization of physiologic substrates, suggesting a robust therapeutic window in humans. This information constitutes an important translational guidance for predicting the therapeutic dose range in clinical studies with PQ912.

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Section: Introductionmentioning

confidence: 85%

Glutaminyl Cyclase Inhibitor PQ912 Improves Cognition in Mouse Models of Alzheimer’s Disease—Studies on Relation to Effective Target Occupancy

Hoffmann

Meyer

Heiser

et al. 2017

J Pharmacol Exp Ther

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“…HJ5.1-biotin (anti-Aβ 13–18 ) (Bero et al, 2011; Liao et al, 2015) was used as the detecting antibody for both Aβ ELISAs. ELISA assays for oligomeric Aβ were performed on fresh PBS-soluble brain homogenates as described previously (Esparza et al, 2016). …”

Section: Star Methodsmentioning

confidence: 99%

Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis

Huynh

Liao

Francis

et al. 2017

Neuron

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156

138

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Summary The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease. Previous studies suggest reduction of apoE levels through genetic manipulation can reduce Aβ pathology. However, it is not clear how reduction of apoE levels after birth would affect amyloid deposition. We utilize an antisense oligonucleotide (ASO) to reduce apoE expression in the brains of APP/PS1-21 mice homozygous for the APOE-ε4 or APOE-ε3 allele. ASO treatment starting after birth led to a significant decrease in Aβ pathology when assessed at 4 months. Interestingly, ASO treatment starting at the onset of amyloid deposition led to an increase in Aβ plaque size and a reduction in plaque-associated neuritic dystrophy with no change in overall plaque load. These results suggest that lowering apoE levels prior to plaque deposition can strongly affect the initiation of Aβ pathology while lowering apoE after Aβ seeding modulates plaque size and toxicity.

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“…For concentration-dependent studies, cells were treated with 500, 1000, and 2000 nM of Aβo for 5 min; or 25, 50, 100, 200, and 400 nM Aβm for 15 min. At the end of treatment time cells were washed two times with ice cold 2% bovine serum albumin (BSA) in phosphate buffer saline (PBS) to minimize non-specific binding of Aβ and once with PBS (Qosa et al, 2014, Esparza et al, 2016). Media and cell lysates were loaded on Aβo and Aβm specific ELISA as described below.…”

Section: Methodsmentioning

confidence: 99%

Oleocanthal ameliorates amyloid-β oligomers’ toxicity on astrocytes and neuronal cells: In vitro studies

et al. 2017

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Extra-virgin olive oil (EVOO) has several health promoting effects. Evidence have shown that EVOO attenuates the pathology of amyloid-β (Aβ) and improves cognitive function in experimental animal models, suggesting it’s potential to protect and reduce the risk of developing Alzheimer’s disease (AD). Available studies have linked this beneficial effect to oleocanthal, one of the active components in EVOO. The effect of oleocanthal against AD pathology has been linked to its ability to attenuate Aβ and tau aggregation in vitro, and enhance Aβ clearance from the brains of wild type and AD transgenic mice in vivo. However, the ability of oleocanthal to alter the toxic effect of Aβ on brain parenchymal cells is unknown. In the current study, we investigated oleocanthal effect on modulating Aβ oligomers (Aβo) pathological events in neurons and astrocytes. Our findings demonstrated oleocanthal prevented Aβo-induced synaptic proteins, SNAP-25 and PSD-95, down-regulation in neurons, and attenuated Aβo-induced inflammation, glutamine transporter (GLT1) and glucose transporter (GLUT1) down-regulation in astrocytes. Aβo-induced inflammation was characterized by interleukin-6 (IL-6) increase and glial fibrillary acidic protein (GFAP) upregulation that were reduced by oleocanthal. In conclusion, this study provides further evidence to support the protective effect of EVOO-derived phenolic secoiridoid oleocanthal against AD pathology.

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Soluble Amyloid-beta Aggregates from Human Alzheimer’s Disease Brains

Cited by 119 publications

References 61 publications

Glutaminyl Cyclase Inhibitor PQ912 Improves Cognition in Mouse Models of Alzheimer’s Disease—Studies on Relation to Effective Target Occupancy

Glutaminyl Cyclase Inhibitor PQ912 Improves Cognition in Mouse Models of Alzheimer’s Disease—Studies on Relation to Effective Target Occupancy

Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis

Oleocanthal ameliorates amyloid-β oligomers’ toxicity on astrocytes and neuronal cells: In vitro studies

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