Trans-Dominant Negative Effects of Pathogenic PSEN1 Mutations on  -Secretase Activity and A  Production

Heilig, Elizabeth; Gutti, Usha; Tai, Tara; Shen, Jie; Kelleher, Raymond J.

doi:10.1523/jneurosci.0954-13.2013

Cited by 71 publications

(90 citation statements)

References 38 publications

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“…We acknowledge the caveat that our experimental conditions, where homogeneous γ-secretase is used in an artificial in vitro setting, are quite different from the complex circumstances in patient brain, where PSEN1 is heterozygous and potential dominant negative effect may be at work (39). Another complicating factor is the in vivo existence of six distinct γ-secretase complexes formed by different forms of presenilin (PS1 and PS2) and APH-1 (APH-1aL, APH-1aS, and APH-1b), which are localized to different regions of the brain (44,63).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to the amyloid hypothesis, the presenilin hypothesis posits that the loss of normal function by the mutant PS1 causes AD through dominant negative effect on the wild-type allele (38,39). This hypothesis provides a satisfactory explanation to the puzzling observation that AD-derived mutations are exclusively missense in nature but not nonsense or frameshift.…”

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase

Sun

Zhou

Yang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

328

323

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A hallmark of Alzheimer's disease (AD) is the aggregation of β-amyloid peptides (Aβ) into amyloid plaques in patient brain. Cleavage of amyloid precursor protein (APP) by the intramembrane protease γ-secretase produces Aβ of varying lengths, of which longer peptides such as Aβ42 are thought to be more harmful. Increased ratios of longer Aβs over shorter ones, exemplified by the ratio of Aβ42 over Aβ40, may lead to formation of amyloid plaques and consequent development of AD. In this study, we analyzed 138 reported mutations in human presenilin-1 (PS1) by individually reconstituting the mutant PS1 proteins into anterior-pharynx-defective protein 1 (APH-1)aL-containing γ-secretases and examining their abilities to produce Aβ42 and Aβ40 in vitro. About 90% of these mutations lead to reduced production of Aβ42 and Aβ40. Notably, 10% of these mutations result in decreased Aβ42/Aβ40 ratios. There is no statistically significant correlation between the Aβ42/Aβ40 ratio produced by a γ-secretase variant containing a specific PS1 mutation and the mean age at onset of patients from whom the mutation was isolated.Alzheimer's disease | γ-secretase | Aβ peptides | cleavage activity | amyloid hypothesis T he first case of Alzheimer's disease (AD) was reported more than 100 y ago, and the brain of the deceased patient contained characteristic senile plaques (1). These plaques were found to be amyloid in nature by electron microscopy (2), and analysis of amino acid sequence revealed the amyloid to be derived from amyloid precursor protein (APP) (3). APP is first cleaved by β-secretase to produce a 99-residue transmembrane fragment C99, which then undergoes additional cleavages by γ-secretase to generate a series of amyloidogenic β-amyloid peptides (Aβ) with 39-43 amino acids (4, 5). The slightly longer Aβ peptides, particularly Aβ42 and Aβ43, are thought to be more prone to aggregation than the shorter ones such as Aβ40 (6-8). Indeed, the amyloid plaques contain mostly longer Aβ peptides such as Aβ42 (9).Familial cases of AD were found to be genetically linked to missense mutations in APP (10, 11). These observations, together with prior knowledge on amyloid plaques, prompted proposition of the amyloid hypothesis, which regards the formation of β-amyloid plaques as the cause of AD through apoptosis induction of neuronal cells (12). Consistent with this hypothesis, Aβ42 was found to induce cell death (13,14). Human presenilin-1 (PS1) was cloned and found to be targeted by missense mutations in early-onset familial AD (EOFAD) (15). Remarkably, these EOFAD-linked PS1 mutants led to elevated molar ratios of Aβ42 over Aβ40 both in cell lines and in the brains of transgenic animals (16), and the plasma levels of Aβ42 and Aβ43 in FAD patients with PS1 or APP mutations were significantly increased compared with those of healthy individuals (17). These observations led to refinement of the amyloid hypothesis, which identifies increased ratios of longer Aβ peptides over shorter ones as a key early event in AD development (18). The increa...

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase

Sun

Zhou

Yang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

328

323

View full text Add to dashboard Cite

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“…Although acne inversa is mediated through a γ-secretase-dependent Notch pathway, Notch1 and Notch2 clearly are not the targets of PS or γ-secretase mediating its function in the adult brain (15). Second, FAD-linked dominantly inherited missense mutations in PS not only have cis-acting effects, reducing its γ-secretase activity, but also have trans-acting effects, inhibiting the γ-secretase activity of the wild-type PS protein (36). Further studies will be needed to elucidate the mechanisms underlying AD and acne inversa, and identification of the γ-secretase substrates responsible for synaptic function and neuronal survival will provide additional mechanistic insight into the role of γ-secretase in the aging brain.…”

Section: Discussionmentioning

confidence: 99%

Synaptic function of nicastrin in hippocampal neurons

Lee

Sharma

Südhof

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Synaptic dysfunction is widely thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Presenilins, the major gene products involved in familial AD, are essential for short-and long-term synaptic plasticity in mature neurons as well as for the survival of cortical neurons during aging. Presenilin and nicastrin are both indispensable components of the γ-secretase complex, but it remains unknown whether presenilin regulates synaptic function in a γ-secretase-dependent or γ-secretase-independent manner and whether nicastrin plays similar roles in central synapses. In the current study, we address these questions using an electrophysiological approach to analyze nicastrin conditional knockout (cKO) mice in the hippocampal Schaffer collateral pathway. In these mice, we found that, even at 2 mo of age, deletion of nicastrin in excitatory neurons of the postnatal forebrain using Cre recombinase expressed under the control of the αCaMKII promoter led to deficits in presynaptic short-term plasticity including paired-pulse facilitation and frequency facilitation. Depletion of Ca 2+ in the endoplasmic reticulum mimics and occludes the presynaptic facilitation deficits in nicastrin cKO mice, suggesting that disrupted intracellular Ca 2+ homeostasis underlies the presynaptic deficits. In addition, NMDA receptor-mediated responses and long-term potentiation induced by theta-burst stimulation were decreased in nicastrin cKO mice at 3 mo but not at 2 mo of age. Together, these findings show that, similar to presenilins, nicastrin plays essential roles in the regulation of short-and longterm synaptic plasticity, highlighting the importance of γ-secretase in the function of mature synapses.A lzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and cognitive decline. The majority of familial AD cases are caused by missense mutations in genes encoding presenilin 1 (PS1) and presenilin 2, which are crucial components of the γ-secretase complex responsible for intramembrane cleavages of type I membrane proteins such as Notch. In addition to presenilin (PS), nicastrin (Nct), presenilin enhancer 2 (Pen-2), and anterior pharynx defective 1 (Aph-1) also are required to form the active γ-secretase complex. Nct is a type-1 transmembrane glycoprotein that originally was identified by its ability to form high molecular weight complexes with PS (1). Nct −/− mice die by embryonic day 10.5 and exhibit patterning defects similar to those in embryos lacking PS or Notch (2-7).In the adult brain, genetic studies using conditional genetargeting approaches demonstrated that both PS and Nct are essential for long-term memory and age-dependent neuronal survival (8-12). These findings highlight the importance of γ-secretase in memory and neuronal survival (13), even though γ-secretase-independent activities of PS have been reported also (14). However, Notch is unlikely to be the key mediator of γ-secretase in the adult brain, because Notch1 and Notch2 conditional knockout (cKO)...

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“…In 2013, Shen, Kelleher, and co-workers published an analysis stated to support a dominant negative interaction between fAD mutant forms of PSEN1 and the wild type (non-mutant) form as would be found in heterozygous individuals possessing dominant fAD mutations [75]. In the study, they co-tranfected constructs expressing mutant and wild type PSEN1 in a 1:1 ratio at (purportedly) sub-saturating levels into mouse embryonic fibroblasts lacking mouse Psen genes.…”

Section: Changes In the Level Of ␥-Secretase Activity Are Criticalmentioning

confidence: 99%

Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease

Jayne

Newman

Verdile

et al. 2016

JAD

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Abstract. The majority of mutations causing familial Alzheimer's disease (fAD) have been found in the gene PRESENILIN1 (PSEN1) with additional mutations in the related gene PRESENILIN2 (PSEN2). The best characterized function of PRESE-NILIN (PSEN) proteins is in ␥-secretase enzyme activity. One substrate of ␥-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (A␤PP/APP) that is a fAD mutation locus. A␤PP is the source of the amyloid-␤ (A␤) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. These observations have resulted in a focus on ␥-secretase activity and A␤ as we attempt to understand the molecular basis of AD pathology. In this paper we briefly review some of the history of research on ␥-secretase in AD. We then discuss the main ideas regarding the role of ␥-secretase and the PSEN genes in this disease. We examine the significance of the "fAD mutation reading frame preservation rule" that applies to PSEN1 and PSEN2 (and A␤PP) and look at alternative roles for A␤PP and A␤ in fAD. We present a case for an alternative interpretation of published data on the role of ␥-secretase activity and fAD-associated mutations in AD pathology. Evidence supports a "PSEN holoprotein multimer hypothesis" where PSEN

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Trans-Dominant Negative Effects of Pathogenic PSEN1 Mutations on -Secretase Activity and A Production

Cited by 71 publications

References 38 publications

Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase

Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase

Synaptic function of nicastrin in hippocampal neurons

Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease

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