P2-053 Reduced β-amyloid burden, increased C-99 concentrations and evaluation of neuropathology in the brains of PDAPP mice given LY450139 dihydrate daily by gavage for 5 months

Ness, Daniel; Boggs, Leonard N.; Hepburn, Deena L.; Gitter, Bruce D.; Long, Gerald G.; May, Patrick C.; Piroozi, Kathy S.; Schafer, Kenneth A.; Yang, Zhihui

doi:10.1016/s0197-4580(04)80800-5

Cited by 29 publications

(21 citation statements)

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“…GSIs are known to reduce A␤ levels in the brain of transgenic Alzheimer mouse models as much as 60% while significantly increasing APP-CTF levels (Dovey et al, 2001;Ness et al, 2004). In our experiments, GSI treatment led to a significant decrease of dendritic spine density in 4-to 6-month-old WT mice, an effect that was not observed in vehicle-treated mice (Figs.…”

Section: Resultssupporting

confidence: 50%

“…DAPT (Millipore Bioscience Research Reagents, Merck) was formulated in 5% (v/v) ethanol and corn oil and subcutaneously administered in 100 mg/kg (Dovey et al, 2001) daily for 4 d. LY450139 was synthesized following the schemes provided by Lilly and formulated in 10% Cremophor EL solution (Sigma-Aldrich), and administered subcutaneously in 30 mg/kg (Ness et al, 2004) daily for 4 d.…”

Section: Mice Appmentioning

confidence: 99%

See 1 more Smart Citation

γ-Secretase Inhibition Reduces Spine DensityIn Vivovia an Amyloid Precursor Protein-Dependent Pathway

Bittner¹,

Fuhrmann²,

Burgold³

et al. 2009

J. Neurosci.

107

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Alzheimer's disease (AD) represents the most common age-related neurodegenerative disorder. It is characterized by the invariant accumulation of the ␤-amyloid peptide (A␤), which mediates synapse loss and cognitive impairment in AD. Current therapeutic approaches concentrate on reducing A␤ levels and amyloid plaque load via modifying or inhibiting the generation of A␤. Based on in vivo two-photon imaging, we present evidence that side effects on the level of dendritic spines may counteract the beneficial potential of these approaches. Two potent ␥-secretase inhibitors (GSIs), DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester) and LY450139 (hydroxylvaleryl monobenzocaprolactam), were found to reduce the density of dendritic spines in wild-type mice. In mice deficient for the amyloid precursor protein (APP), both GSIs had no effect on dendritic spine density, demonstrating that ␥-secretase inhibition decreases dendritic spine density via APP. Independent of the effects of ␥-secretase inhibition, we observed a twofold higher density of dendritic spines in the cerebral cortex of adult APP-deficient mice. This observation further supports the notion that APP is involved in the modulation of dendritic spine density-shown here for the first time in vivo.

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Section: Resultssupporting

confidence: 50%

Section: Mice Appmentioning

confidence: 99%

γ-Secretase Inhibition Reduces Spine DensityIn Vivovia an Amyloid Precursor Protein-Dependent Pathway

Bittner¹,

Fuhrmann²,

Burgold³

et al. 2009

J. Neurosci.

107

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show abstract

“…In rodents, early treatment with g-secretase inhibitor can prevent or ameliorate Aβ deposition but established SP [1] and hyperphosphorylated tau aggregates [99] appear more resistant. In this regard, the failure of semagacestat in clinical trials, a well-characterised g-secretase inhibitor, was particularly notable as Aβ deposition was reduced by this compound in both transgenic mice and humans [95].…”

Section: Evidence From Transgenic Experimentsmentioning

confidence: 99%

A critical analysis of the ‘amyloid cascade hypothesis’

Armstrong¹

2014

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A b s t r a c t The 'amyloid cascade hypothesis' (ACH) is the most influential model of the pathogenesis of Alzheimer's disease (AD). The hypothesis proposes that the deposition of β-amyloid (Aβ) is the initial pathological event in AD, leading to the formation of extracellular senile plaques (SP), tau-immunoreactive neurofibrillary tangles (NFT), neuronal loss, and ultimately, clinical dementia. Ever since the formulation of the ACH, however, there have been questions regarding whether it completely describes AD pathogenesis. This review critically examines various aspects of the ACH including its origin and development, the role of amyloid precursor protein (APP), whether SP and NFT are related to the development of clinical dementia, whether Aβ and tau are 'reactive' proteins, and whether there is a pathogenic relationship between SP and NFT. The results of transgenic experiments and treatments for AD designed on the basis of the ACH are also reviewed. It was concluded: (1) Aβ and tau could be the products rather than the cause of neurodegeneration in AD, (2) it is doubtful whether there is a direct causal link between Aβ and tau, and (3) SP and NFT may not be directly related to the development of dementia, (4) transgenic models involving

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“…These mice express high levels of human mutant APP and progressively develop many of the patholog-ical hallmarks of AD (Games et al, 1995). In a study of PDAPP mice treated with semagacestat, accumulation of A␤ in the brains was slowed during 5 months of treatment (Ness et al, 2004). Clinical studies in healthy volunteers and in AD patients treated with semagacestat also indicated a dose-dependent decrease of plasma A␤ (Siemers et al, 2005(Siemers et al, , 2006(Siemers et al, , 2007.…”

mentioning

confidence: 99%

Disposition and Metabolism of Semagacestat, a γ-Secretase Inhibitor, in Humans

Yi¹,

Hadden²,

Kulanthaivel³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Semagacestat is a functional ␥-secretase inhibitor that has been shown to reduce the rate of formation of amyloid-␤ in vitro and in vivo. This study was conducted to characterize the disposition of semagacestat in humans. After a single 140-mg dose of [ 14 C]semagacestat administered as an oral solution to six healthy male subjects, semagacestat was rapidly absorbed (T max ϳ0.5 h) and eliminated from the systemic circulation (terminal t 1/2 ϳ2.4 h). The major circulating metabolites of semagacestat, M2 (hydrolysis of the amide bond proximal to the benzazepine ring) and M3 (benzylic hydroxylation of the benzazepine ring), accounted for approximately 27 and 10% of total radioactivity exposure, respectively, as calculated from relative area under the plasma concentration versus time curve from 0 to 24 h derived from the plasma radiochro- Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by cognitive impairment. The prevalence rate is approximately 6% among those aged more than 65 years. Currently more than 4 million Americans suffer from AD, and this number is expected to quadruple by year 2050 as average lifespan increases (Rice et al., 2001;Joyce et al., 2007). AD has a substantial impact on patients, caregivers, and the healthcare system. Average total medical costs for AD patients are more than 5-fold higher than those for control populations. Development of pharmaceuticals for the treatment of AD would greatly benefit AD patients and society. The cause of AD is not yet clear. Pathological studies revealed the existence of neuritic plaques in the brains of AD patients (Desai and Grossberg, 2005;Blennow et al., 2006). The plaques are mainly composed of amyloid-␤ (A␤) peptides that are formed by the sequential cleavage of the amyloid precursor protein (APP). APP is first cleaved by the ␤-site APP-cleaving enzyme to form the N terminus of A␤, which is further cleaved by ␥-secretase at multiple sites to form A␤ isoforms ranging from 37 (A␤37) to 43 (A␤43) residues (Olson and Albright, 2008). Mutations in APP near cleavage sites resulting in the A␤ formation have been linked to AD in several families (Selkoe, 2001;Imbimbo, 2008). This observation suggests that a reduction in A␤ synthesis could slow the disease progression in patients with AD.Semagacestat, an azepine class ␥-secretase inhibitor, is one of a very few ␥-secretase inhibitors that have been advanced into clinical trials as potential disease-modifying agents for the treatment of AD (Olson and Albright, 2008). Semagacestat reduces the rate of formation of A␤ in whole cell assays, as well as in transgenic and nontransgenic mice, beagle dogs, and guinea pigs Hyslop et al., 2004;May et al., 2004;Lanz et al., 2006). A transgenic mouse model of AD was generated using a platelet-derived growth factor ␤ promoter driving a human APP minigene encoding the APP V171F mutation (PDAPP mouse). These mice express high levels of human mutant APP and progressively develop many of the pathologArticle, publication date, and citation ...

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P2-053 Reduced β-amyloid burden, increased C-99 concentrations and evaluation of neuropathology in the brains of PDAPP mice given LY450139 dihydrate daily by gavage for 5 months

Cited by 29 publications

References 0 publications

γ-Secretase Inhibition Reduces Spine DensityIn Vivovia an Amyloid Precursor Protein-Dependent Pathway

γ-Secretase Inhibition Reduces Spine DensityIn Vivovia an Amyloid Precursor Protein-Dependent Pathway

A critical analysis of the ‘amyloid cascade hypothesis’

Disposition and Metabolism of Semagacestat, a γ-Secretase Inhibitor, in Humans

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