Article

The mechanism of γ-Secretase dysfunction in familial Alzheimer disease

VIB Center for the Biology of Disease, Leuven, Belgium.
The EMBO Journal (Impact Factor: 10.43). 04/2012; 31(10):2261-74. DOI: 10.1038/emboj.2012.79
Source: PubMed

ABSTRACT

The mechanisms by which mutations in the presenilins (PSEN) or the amyloid precursor protein (APP) genes cause familial Alzheimer disease (FAD) are controversial. FAD mutations increase the release of amyloid β (Aβ)42 relative to Aβ40 by an unknown, possibly gain-of-toxic-function, mechanism. However, many PSEN mutations paradoxically impair γ-secretase and 'loss-of-function' mechanisms have also been postulated. Here, we use kinetic studies to demonstrate that FAD mutations affect Aβ generation via three different mechanisms, resulting in qualitative changes in the Aβ profiles, which are not limited to Aβ42. Loss of ɛ-cleavage function is not generally observed among FAD mutants. On the other hand, γ-secretase inhibitors used in the clinic appear to block the initial ɛ-cleavage step, but unexpectedly affect more selectively Notch than APP processing, while modulators act as activators of the carboxypeptidase-like (γ) activity. Overall, we provide a coherent explanation for the effect of different FAD mutations, demonstrating the importance of qualitative rather than quantitative changes in the Aβ products, and suggest fundamental improvements for current drug development efforts.

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    • "We have demonstrated that loss of endopeptidase activity is not necessarily observed in γ-secretase complexes containing PSEN1/2 FAD-linked mutations, but reduced carboxypeptidase-like efficiency (γ-secretase dysfunction) is the constant denominator. Furthermore, FAD PSEN mutations may affect the carboxypeptidase-like γ-secretase activity at multiple turnovers, resulting in increased Aβ43 and Aβ42 levels as well as in other longer Aβ peptides, such as Aβ45 and Aβ46 (Quintero-Monzon et al., 2011; Chávez-Gutiérrez et al., 2012; Fernandez et al., 2014). These data support a model in which relative, rather than absolute, changes in Aβ product profiles are at the basis of PSEN/γ-secretase–mediated pathogenicity. "
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    ABSTRACT: Presenilin (PSEN) pathogenic mutations cause familial Alzheimer's disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed gamma-secretase activity in brain samples from 15 nondemented subjects, 22 FAD patients harboring nine different mutations in PSEN1, and 11 sporadic AD (SAD) patients. FAD and control brain samples had similar overall gamma-secretase activity levels, and therefore, loss of overall (endopeptidase) gamma-secretase function cannot be an essential part of the pathogenic mechanism. In contrast, impaired carboxypeptidase-like activity (gamma-secretase dysfunction) is a constant feature in all FAD brains. Significantly, we demonstrate that pharmacological activation of the carboxypeptidase-like gamma-secretase activity with gamma-secretase modulators alleviates the mutant PSEN pathogenic effects. Most SAD cases display normal endo- and carboxypeptidase-like gamma-secretase activities. However and interestingly, a few SAD patient samples display gamma-secretase dysfunction, suggesting that gamma-secretase may play a role in some SAD cases. In conclusion, our study highlights qualitative shifts in amyloid-beta (Abeta) profiles as the common denominator in FAD and supports a model in which the healthy allele contributes with normal Abeta products and the diseased allele generates longer aggregation-prone peptides that act as seeds inducing toxic amyloid conformations.
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    • "Although rare, mutation-linked neurodegeneration cases provide invaluable hints that can help decipher the mechanisms that underlie the development of these maladies. Interestingly, many AD-causing mutations in the sequence of PS1 do not elevate total Ab levels (Chavez-Gutierrez et al, 2012), suggesting that noncanonical mechanisms are accountable for the development of certain AD cases by attenuating PS1 function. Moreover, while most PS1 mutations cause familial AD (fAD), certain amino acid substations in the sequence of PS1 were reported to initiate FTD (Mendez & McMurtray, 2006). "
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    ABSTRACT: Do different neurodegenerative maladies emanate from the failure of a mutual protein folding mechanism? We have addressed this question by comparing mutational patterns that are linked to the manifestation of distinct neurodegenerative disorders and identified similar neurodegeneration-linked proline substitutions in the prion protein and in presenilin 1 that underlie the development of a prion disorder and of familial Alzheimer's disease (fAD), respectively. These substitutions were found to prevent the endoplasmic reticulum (ER)-resident chaperone, cyclophilin B, from assisting presenilin 1 to fold properly, leading to its aggregation, deposition in the ER, reduction of c-secretase activity, and impaired mito-chondrial distribution and function. Similarly, reduced quantities of the processed, active presenilin 1 were observed in brains of cyclophilin B knockout mice. These discoveries imply that reduced cyclophilin activity contributes to the development of distinct neurodegenerative disorders, propose a novel mechanism for the development of certain fAD cases, and support the emerging theme that this disorder can stem from aberrant presenilin 1 function. This study also points at ER chaperones as targets for the development of counter-neurodegeneration therapies.
    Full-text · Article · Oct 2015 · The EMBO Journal
    • "We have demonstrated that loss of endopeptidase activity is not necessarily observed in γ-secretase complexes containing PSEN1/2 FAD-linked mutations, but reduced carboxypeptidase-like efficiency (γ-secretase dysfunction) is the constant denominator. Furthermore, FAD PSEN mutations may affect the carboxypeptidase-like γ-secretase activity at multiple turnovers, resulting in increased Aβ43 and Aβ42 levels as well as in other longer Aβ peptides, such as Aβ45 and Aβ46 (Quintero-Monzon et al., 2011; Chávez-Gutiérrez et al., 2012; Fernandez et al., 2014). These data support a model in which relative, rather than absolute, changes in Aβ product profiles are at the basis of PSEN/γ-secretase–mediated pathogenicity. "

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