A Noncompetitive BACE1 Inhibitor TAK-070 Ameliorates Aβ Pathology and Behavioral Deficits in a Mouse Model of Alzheimer's Disease

Fukumoto, Hiroaki; Takahashi, Hideki; Tarui, Naoki; Matsui, Junji; Tomita, Taisuke; Hirode, Mitsuhiro; Sagayama, Masumi; Maeda, Ryouta; Kawamoto, Masuki; Hirai, Kazuko; Terauchi, Jun; Sakura, Yasufumi; Kakihana, Mitsuru; Kato, Keita; Iwatsubo, Takeshi; Miyamoto, Masaomi

doi:10.1523/jneurosci.2884-10.2010

Cited by 121 publications

(89 citation statements)

References 43 publications

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“…BACE inhibitors applied in cell culture have sometimes led to apparent shunting of APP down the ␣-secretase pathway resulting in increased sAPP␣ secretion (Hussain et al, 2007;Fukumoto et al, 2010), but not always (Kim et al, 2008). This has contrasted with human studies that seemed to indicate a noncompetitive relationship between the ␣-secretase and BACE APP processing pathways (Gabelle et al, 2010;Lewczuk et al, 2010;Alexopolous et al, 2012;Dobrowolska et al, 2014). Our reported baseline positive correlation of sAPP␣ and sAPP␤ further supports this.…”

Section: Discussionmentioning

confidence: 99%

“…They conform to the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, National Research Council, 1996). The cisterna magna ported (CMP) stable catheterization procedures and CSF flow and collection, as well as the vascular access port infusion protocol, were as described previously (Gilberto et al, 2003;.…”

Section: Cisterna Magna Ported Conscious Nhp Modelmentioning

confidence: 99%

“…Compared with peripheral, non-CNS tissues, CNS APP processing demonstrates increased ␤-secretase (BACE) activity (Irizarry et al, 2001;Fukumoto et al, 2002) and different responses to ␥-secretase modulation . The differences between APP processing in the CNS and peripheral compartments are not fully understood (Ortega et al, 2013); further understanding of APP processing may be important to inform the design and development of Alzheimer's disease (AD) therapeutics.…”

Section: Introductionmentioning

confidence: 99%

“…BACE1 appears to be the predominant BACE in the CNS and is located mainly in the membranes of cellular compartments. BACE1 may be increased ϳ2-fold in brains (Fukumoto et al, 2002;Li et al, 2004;Yang et al, 2003) or CSF of AD patients (Holsinger et al, 2006;Verheijen et al, 2006;, although recent reports suggest little change from healthy controls Rosén et al, 2012;. Brain penetrant BACE1 inhibitors capable of lowering CNS A␤ in rodent and nonhuman primate (NHP) models (Sankaranarayanan et al, 2009;Malamas et al, 2010;Takahashi et al, 2010;Truong et al, 2010;Mandal et al, 2012;Stamford et al, 2012) have been identified and multiple BACE inhibitors have advanced into early stages of human clinical trials (May et al, 2011;Egan et al, 2012, Forman et al, 2013Bernier et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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CNS Amyloid- , Soluble APP- and - Kinetics during BACE Inhibition

Dobrowolska¹,

Michener²,

et al. 2014

Journal of Neuroscience

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BACE, a ␤-secretase, is an attractive potential disease-modifying therapeutic strategy for Alzheimer's disease (AD) as it results directly in the decrease of amyloid precursor protein (APP) processing through the ␤-secretase pathway and a lowering of CNS amyloid-␤ (A␤) levels. The interaction of the ␤-secretase and ␣-secretase pathway-mediated processing of APP in the rhesus monkey (nonhuman primate; NHP) CNS is not understood. We hypothesized that CNS inhibition of BACE would result in decreased newly generated A␤ and soluble APP␤ (sAPP␤), with increased newly generated sAPP␣.A stable isotope labeling kinetics experiment in NHPs was performed with a 13 C 6 -leucine infusion protocol to evaluate effects of BACE inhibition on CNS APP processing by measuring the kinetics of sAPP␣, sAPP␤, and A␤ in CSF. Each NHP received a low, medium, or high dose of MBI-5 (BACE inhibitor) or vehicle in a four-way crossover design. CSF sAPP␣, sAPP␤, and A␤ were measured by ELISA and newly incorporated label following immunoprecipitation and liquid chromatography-mass spectrometry. Concentrations, kinetics, and amount of newly generated APP fragments were calculated. sAPP␤ and sAPP␣ kinetics were similar, but both significantly slower than A␤. BACE inhibition resulted in decreased labeled sAPP␤ and A␤ in CSF, without observable changes in labeled CSF sAPP␣. ELISA concentrations of sAPP␤ and A␤ both decreased and sAPP␣ increased. sAPP␣ increased by ELISA, with no difference by labeled sAPP␣ kinetics indicating increases in product may be due to APP shunting from the ␤-secretase to the ␣-secretase pathway. These results provide a quantitative understanding of pharmacodynamic effects of BACE inhibition on NHP CNS, which can inform about target development.

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Section: Discussionmentioning

confidence: 99%

Section: Cisterna Magna Ported Conscious Nhp Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

CNS Amyloid- , Soluble APP- and - Kinetics during BACE Inhibition

Dobrowolska¹,

Michener²,

et al. 2014

Journal of Neuroscience

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show abstract

“…Knock-out animals lacking the catalytic components of γ-secretase (PSEN1 or PSEN2) fail to develop in to viable embryos, while gene knock-out of β-secretase is well tolerated (Luo et al 2001). Despite this, and despite promising results of BACE1 inhibitors in animal models (Fukumoto et al 2010;Chang et al 2011), very few β-secretase targeted therapies have reached clinical trial. One promising result was obtained in the case of CTS-21166, a well tolerated BACE1 inhibitor which passed phase I clinical trials in humans, eliciting a dose dependent decrease in plasma Aβ levels, although little has been published on the molecule (Panza et al 2009).…”

Section: Aβ Related Treatmentsmentioning

confidence: 99%

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

Lord

Turton

Braae

et al. 2014

Alzheimer's & Dementia

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In 2009, two large genome wide association studies (GWAS) found associations between common single nucleotide polymorphisms (SNPs) at three loci (CLU, PICALM and CR1) and Alzheimer's disease (AD) risk. The causal variants underlying these associations and how these impact on AD susceptibility remain unclear. Target enrichment and next generation sequencing (NGS) were used to completely resequence the three associated loci in 96 AD patients in an attempt to uncover potentially causative and rare variants that may explain the observed association signals. A pipeline was developed for the handling of pooled NGS data following a comparison of several different combinations of programs. 33 exonic SNPs were found within the three genes, along with over 1000 non-coding variants. To identify the variants most likely to be affecting AD risk, a two pronged approach was adopted. The variants were imputed in a large case-control cohort (2067 cases, 7376 controls) to test for association with AD, and the likely functional consequences of the variants were assessed using in silico resources. Several of the analysed variants showed suggestive or significant association with AD in the imputed data, and/or were predicted to have consequences on the function or regulation of the genes, suggesting avenues for future research in AD genetics. The whole method of pooled, targeted NGS and prioritisation using imputed data for association testing and in silico resources for functional analysis represents a new strategy for tracking down the illusive causation of GWAS signals. PublicationsNext generation sequencing of CLU, PICALM and CR1: pitfalls and potential solutions. Lord J,

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Transgenic amyloid precursor protein mouse models of amyloidosis. Incomplete models for Alzheimer's disease but effective predictors of anti‐amyloid therapies

Morgan,

Lamb

2023

Alzheimer's & Dementia

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INTRODUCTIONAmyloid precursor protein (APP) transgenic mice are models of Alzheimer's disease (AD) amyloidosis, not all of AD. Diffuse, compacted, and vascular deposits in APP mice mimic those found in AD cases.METHODSMost interventional studies in APP mice start treatment early in the process of amyloid deposition, consistent with a prevention treatment regimen. Most clinical trials treat patients with established amyloid deposits in a therapeutic treatment regimen.RESULTSThe first treatment to reduce amyloid and cognitive impairment in mice was immunotherapy. The APP mouse models not only predicted efficacy, but presaged the vascular leakage called ARIA. The recent immunotherapy clinical trials that removed amyloid and slowed cognitive decline confirms the utility of these early APP models when used in therapeutic designs.DISCUSSIONNew mouse models of AD pathologies will add to the research armamentarium, but the early models have accurately predicted responses to amyloid therapies in humans.

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A Noncompetitive BACE1 Inhibitor TAK-070 Ameliorates Aβ Pathology and Behavioral Deficits in a Mouse Model of Alzheimer's Disease

Cited by 121 publications

References 43 publications

CNS Amyloid- , Soluble APP- and - Kinetics during BACE Inhibition

CNS Amyloid- , Soluble APP- and - Kinetics during BACE Inhibition

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

Transgenic amyloid precursor protein mouse models of amyloidosis. Incomplete models for Alzheimer's disease but effective predictors of anti‐amyloid therapies

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