Reciprocal relationship between APP positioning relative to the membrane and PS1 conformation

Uemura, Kazunori; Farner, Katherine C.; Nasser-Ghodsi, Navine; Jones, Phillip John; Berezovska, Oksana

doi:10.1186/1750-1326-6-15

Cited by 20 publications

(19 citation statements)

References 47 publications

(68 reference statements)

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“…Our results can further strengthen earlier proposals that multiple substrate molecules can bind to γ-secretase at the same time and modulate its activity [10], as well as earlier observations that saturation of γ-secretase with its substrate can affect its interaction with different inhibitors [14], [17], [26]–[29], [35], [52], [59]. It has been suggested that the biphasic inhibition is not a result of allosteric regulation since this type of inhibition can be observed with very different inhibitors, including the transition state inhibitors that target the active site aspartates [14], [70].…”

Section: Discussionsupporting

confidence: 91%

“…The new insights are combined in one molecular mechanism (Figs. 1,2,3,4), that is fully consistent with the previous descriptions of γ-secretase interaction with its substrate and its different inhibitors [9], [10], [14]–[17], [26]–[29], [35], [52], [54], [55], [59]. The biphasic dose-response primarily affects potentially pathogenic β-secretase → γ-secretase branch of APP metabolism [14].…”

Section: Discussionsupporting

confidence: 87%

“…2); iv ) novel improved inhibitors can be prepared from the compounds that bind to multiple sites on γ-secretase simultaneously. We propose that some of our conclusions on DAPT could be extrapolated to the other biphasic inhibitors of γ-secretase, based on a high degree of numerical and conceptual consistency between our studies and the related studies in the past [9], [10], [14]–[17], [26]–[29], [35], [52], [54], [55], [59].…”

Section: Discussionsupporting

confidence: 56%

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Modulators of γ-Secretase Activity Can Facilitate the Toxic Side-Effects and Pathogenesis of Alzheimer's Disease

2013

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BackgroundSelective modulation of different Aβ products of an intramembrane protease γ-secretase, could be the most promising strategy for development of effective therapies for Alzheimer's disease. We describe how different drug-candidates can modulate γ-secretase activity in cells, by studying how DAPT affects changes in γ-secretase activity caused by gradual increase in Aβ metabolism.ResultsAβ 1–40 secretion in the presence of DAPT shows biphasic activation-inhibition dose-response curves. The biphasic mechanism is a result of modulation of γ-secretase activity by multiple substrate and inhibitor molecules that can bind to the enzyme simultaneously. The activation is due to an increase in γ-secretase's kinetic affinity for its substrate, which can make the enzyme increasingly more saturated with otherwise sub-saturating substrate. The noncompetitive inhibition that prevails at the saturating substrate can decrease the maximal activity. The synergistic activation-inhibition effects can drastically reduce γ-secretase's capacity to process its physiological substrates. This reduction makes the biphasic inhibitors exceptionally prone to the toxic side-effects and potentially pathogenic. Without the modulation, γ-secretase activity on it physiological substrate in cells is only 14% of its maximal activity, and far below the saturation.SignificancePresented mechanism can explain why moderate inhibition of γ-secretase cannot lead to effective therapies, the pharmacodynamics of Aβ-rebound phenomenon, and recent failures of the major drug-candidates such as semagacestat. Novel improved drug-candidates can be prepared from competitive inhibitors that can bind to different sites on γ-secretase simultaneously. Our quantitative analysis of the catalytic capacity can facilitate the future studies of the therapeutic potential of γ-secretase and the pathogenic changes in Aβ metabolism.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 56%

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Modulators of γ-Secretase Activity Can Facilitate the Toxic Side-Effects and Pathogenesis of Alzheimer's Disease

2013

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“…More than 160 mutations have been identified that are located throughout the entire sequence of the PS1 molecule and are associated with early-onset familial AD (fAD) [Alzheimer Disease & Frontotemporal Dementia Mutation Database: http://www.molgen.ua.ac.be/ADMutations10]. We have previously shown that fAD-linked mutations in PS1 lead to a consistent change in PS1 conformation, alter APP positioning within the membrane, and affect PS1/-secretase alignment with the APP substrate [4,67]. Using a variety of genetic and pharmacological manipulations, others and we have established that changes in conformation of PS1 are associated with shifts in the A 42/40 ratio [28,4,42,61].…”

Section: Introductionmentioning

confidence: 99%

Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer’s disease

et al. 2012

Self Cite

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Accumulation of amyloid-β (Aβ) and neurofibrillary tangles in the brain, inflammation and synaptic and neuronal loss are some of the major neuropathological hallmarks of Alzheimer’s disease (AD). While genetic mutations in amyloid precursor protein and presenilin-1 and -2 (PS1 and PS2) genes cause early-onset familial AD, the etiology of sporadic AD is not fully understood. Our current study shows that changes in conformation of endogenous wild type PS1, similar to those found with mutant PS1, occur in sporadic AD brain and during normal aging. Using a mouse model of Alzheimer’s disease (Tg2576) that overexpresses the Swedish mutation of amyloid precursor protein but has normal levels of endogenous wild-type presenilin, we report that the percentage of PS1 in a pathogenic conformation increases with age. Importantly, we found that this PS1 conformational shift is associated with amyloid pathology and precedes amyloid-β deposition in the brain. Furthermore, we found that oxidative stress, a common stress characteristic of aging and AD, causes pathogenic PS1 conformational change in neurons in vitro, which is accompanied by increased A 42/40 ratio. The results of this study provide important information about the timeline of pathogenic changes in PS1 conformation during aging, and suggest that structural changes in PS1/-secretase may represent a molecular mechanism by which oxidative stress triggers amyloid-β accumulation in aging and in sporadic AD brain.

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“…PSEN mutations cause abnormal processing of APP and lead to early onset AD [107-109]. Therefore, PSEN gene regulation may play a crucial role in the development of AD.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation and its misregulation in Alzheimer’s disease

Chen

Zhang

et al. 2013

Mol Brain

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by loss of memory and cognitive function. A key neuropathological event in AD is the accumulation of amyloid-β (Aβ) peptide. The production and clearance of Aβ in the brain are regulated by a large group of genes. The expression levels of these genes must be fine-tuned in the brain to keep Aβ at a balanced amount under physiological condition. Misregulation of AD genes has been found to either increase AD risk or accelerate the disease progression. In recent years, important progress has been made in uncovering the regulatory elements and transcriptional factors that guide the expression of these genes. In this review, we describe the mechanisms of transcriptional regulation for the known AD genes and the misregualtion that leads to AD susceptibility.

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Reciprocal relationship between APP positioning relative to the membrane and PS1 conformation

Cited by 20 publications

References 47 publications

Modulators of γ-Secretase Activity Can Facilitate the Toxic Side-Effects and Pathogenesis of Alzheimer's Disease

Modulators of γ-Secretase Activity Can Facilitate the Toxic Side-Effects and Pathogenesis of Alzheimer's Disease

Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer’s disease

Transcriptional regulation and its misregulation in Alzheimer’s disease

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