Gamma-secretase: structure, function, and modulation for Alzheimer's disease.

Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
Current topics in medicinal chemistry (Impact Factor: 3.4). 02/2008; 8(1):2-8.
Source: PubMed


Gamma-secretase proteolyzes a variety of membrane-associated fragments derived from type I integral membrane proteins, including the amyloid beta-protein precursor, involved in Alzheimer's disease, and the Notch receptor, critical for cellular differentiation. This protease is composed of four integral membrane proteins: presenilin, nicastrin, Aph-1 and Pen-2. Assembly of these four components leads to presenilin autoproteolysis into two subunits, each of which contributes one aspartate to the active site of an aspartyl protease. The protease contains an initial docking site for substrate, where it binds prior to passing between the two presenilin subunits to the internal water-containing active site. The extracellular region of nicastrin also interacts with the N-terminus of the substrate as an essential step in substrate recognition and processing. Modulation of APP processing without interfering with Notch signaling is an important therapeutic goal, and allosteric sites on the protease allow such selective modulation. A better structural and mechanistic understanding of gamma-secretase should ultimately allow structure-based design of more potent and selective modulators.

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    • "The combined activity of β- and γ-secretase activities releases Aβ peptides of various lengths [5]. The γ-secretase comprises a high molecular weight complex that depends on presenilin-1 and -2 (PS1, PS2) activity to cleave within the transmembrane domain of APP to generate Aβ peptides and is composed of four integral membrane proteins: presenilin, nicastrin, Aph-1 and Pen-2 [6]. Supporting the amyloid hypothesis, autosomal dominant mutations in APP, PS1 and PS2 genes cause familial early onset AD mainly by increasing the production of Aβx-42[7]. "
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    ABSTRACT: According to the modified amyloid hypothesis the main event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid beta-peptide (Abeta) within neurons. Additionally to full-length peptides, a great diversity of N-truncated Abeta variants is derived from the larger amyloid precursor protein (APP). Vast evidence suggests that Abetax-42 isoforms play an important role triggering neurodegeneration due to its high abundance, amyloidogenic propensity and toxicity. Although N-truncated and Abetax-42 species have been pointed as crucial players in AD etiology, the Abeta5-x isoforms have not received much attention. The present study is the first to show immunohistochemical evidence of Abeta5-x in familial cases of AD (FAD) and its distribution in APP/PS1KI, 5XFAD and 3xTG transgenic mouse models. In order to probe Abeta5-x peptides we generated the AB5-3 antibody. Positive plaques and congophilic amyloid angiopathy (CAA) were observed among all the FAD cases tested carrying either APP or presenilin 1 (PS1) mutations and most of the sporadic cases of AD (SAD). Different patterns of Abeta5-x distribution were found in the mouse models carrying different combinations of autosomal mutations in the APP, PS1 and Tau genes. All of them showed extracellular Abeta deposits but none CAA. Additionally, they were all affected by a severe amyloid pathology in the hippocampus among other areas. Interestingly, neither 5XFAD nor APP/PS1KI showed any evidence for intraneuronal Abeta5-x. Different degrees of Abeta5-x accumulations can be found in the transgenic AD mouse models and human cases expressing the sporadic or the familial form of the disease. Due to the lack of intracellular Abeta5-x, these isoforms might not be contributing to early mechanisms in the cascade of events triggering AD pathology. Brain sections obtained from SAD cases showed higher Abeta5-x-immunoreactivity in vascular deposits than in extracellular plaques, while both are equally important in the FAD cases. The difference may rely on alternative mechanisms involving Abeta5-x peptides and operating in a divergent way in the late and early onset forms of the disease.
    Molecular Neurodegeneration 04/2014; 9(1):13. DOI:10.1186/1750-1326-9-13 · 6.56 Impact Factor
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    • "In addition to APP, γ-secretase processes more than 20 other substrates that participate in a diverse array of biological functions [11] such as cell-to-cell adhesion [12], differentiation [13], [14], and angiogenesis [15]. Vascular stability is one of the more consequential processes that rely on γ-secretase activity, by way of Notch signaling [16]. "
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    ABSTRACT: Alzheimer's disease research has been at an impasse in recent years with lingering questions about the involvement of Amyloid-β (Aβ). Early versions of the amyloid hypothesis considered Aβ something of an undesirable byproduct of APP processing that wreaks havoc on the human neocortex, yet evolutionary conservation--over three hundred million years--indicates this peptide plays an important biological role in survival and reproductive fitness. Here we describe how Aβ regulates blood vessel branching in tissues as varied as human umbilical vein and zebrafish hindbrain. High physiological concentrations of Aβ monomer induced angiogenesis by a conserved mechanism that blocks γ-secretase processing of a Notch intermediate, NEXT, and reduces the expression of downstream Notch target genes. Our findings allude to an integration of signaling pathways that utilize γ-secretase activity, which may have significant implications for our understanding of Alzheimer's pathogenesis vis-à-vis vascular changes that set the stage for ensuing neurodegeneration.
    PLoS ONE 07/2012; 7(7):e39598. DOI:10.1371/journal.pone.0039598 · 3.23 Impact Factor
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    • "These findings suggest a pathway for γ-secretase substrate from docking site to active site: upon binding to the outer surface of presenilin at the NTF/CTF interface, the substrate can pass between these two presenilin subunits to access the internal active site. γ-Secretase has in many ways been an attractive target for Alzheimer therapeutics (Wolfe, 2008), with one inhibitor (compound 3, Figure 2) now in advanced clinical trials (Siemers et al., 2007). However, interference with Notch processing and signalling may lead to toxicities that preclude clinical use of such inhibitors. "
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    ABSTRACT: Presenilin is the catalytic component of gamma-secretase, a complex aspartyl protease and a founding member of intramembrane-cleaving proteases. gamma-Secretase is involved in the pathogenesis of Alzheimer's disease and a top target for therapeutic intervention. However, the protease complex processes a variety of transmembrane substrates, including the Notch receptor, raising concerns about toxicity. Nevertheless, gamma-secretase inhibitors and modulators have been identified that allow Notch processing and signaling to continue, and promising compounds are entering clinical trials. Molecular and biochemical studies offer a model for how this protease hydrolyzes transmembrane domains in the confines of the lipid bilayer. Progress has also been made toward structure elucidation of presenilin and the gamma-secretase complex by electron microscopy as well as by studying cysteine-mutant presenilins. The signal peptide peptidase (SPP) family of proteases are distantly related to presenilins. However, the SPPs work as single polypeptides without the need for cofactors and otherwise appear to be simple model systems for presenilin in the gamma-secretase complex. SPP biology, structure, and inhibition will also be discussed.
    Biological Chemistry 08/2010; 391(8):839-47. DOI:10.1515/BC.2010.086 · 3.27 Impact Factor
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