The AβCs of Aβ-cleaving Proteases

Leissring, Malcolm A.

doi:10.1074/jbc.r800022200

Cited by 76 publications

(61 citation statements)

References 48 publications

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“…64 Of the described mechanism of Ab catabolism, 65 the observed effect could be attributed to metalloproteinases (MMPs). MMP activity, mainly in astrocytes and microglia, is able to degrade oligomeric and fibrillar aggregates.…”

Section: Discussionmentioning

confidence: 99%

“…MMP activity, mainly in astrocytes and microglia, is able to degrade oligomeric and fibrillar aggregates. [65][66][67] Furthermore, MMP-2 and MMP-9 are identified as Wnt target genes in T cells; 68 MMP-7 is a Wnt target gene in colon rectal cancer. 69,70 Moreover, the inhibition of GSK-3b by Akt leads to an increased level in the activity of MMP.…”

Section: Discussionmentioning

confidence: 99%

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Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer's disease

2009

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer's disease

2009

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“…As a consequence, ECEs primarily degrade Ab at intracellular sites ). This point is important, because, together with other evidence (Leissring 2008), it serves to show that the vast majority of Ab degradation likely occurs before the secretion of the monomer into the extracellular space.…”

Section: Endothelin-converting Enzymesmentioning

confidence: 99%

“…Abundant evidence shows that AbDPs, both collectively and in many cases individually, contribute substantially to the determination of cerebral Ab levels (Eckman and Eckman 2005;Leissring 2008; Leissring and Saido 2007;Turner and Nalivaeva 2007). In an illustrative study, the half-life of Ab in brain interstitial fluid (ISF) was quantified in APP transgenic mice lacking or expressing NEP ( Fig.…”

Section: General Features Ab Levels Are Potently Regulated By Proteolmentioning

confidence: 99%

Proteolytic Degradation of Amyloid -Protein

Saido

Leissring²

2012

Cold Spring Harbor Perspectives in Medicine

305

269

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The amyloid b-protein (Ab) is subject to proteolytic degradation by a diverse array of peptidases and proteinases, known collectively as Ab-degrading proteases (AbDPs). A growing number of AbDPs have been identified, which, under physiological and/or pathophysiological conditions, contribute significantly to the determination of endogenous cerebral Ab levels. Despite more than a decade of investigation, the complete set of AbDPs remains to be established, and our understanding of even well-established AbDPs is incomplete. Nevertheless, the study of known AbDPs has contributed importantly to our understanding of the molecular pathogenesis of Alzheimer disease (AD) and has inspired the development of several novel therapeutic approaches to the regulation of cerebral Ab levels. In this article, we discuss the general features of Ab degradation and introduce the best-characterized AbDPs, focusing on their diverse properties and the numerous conceptual insights that have emerged from the study of each.

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“…To examine this hypothesis, we sought to induce selective removal of A␤42 monomers using IDE, an enzyme that selectively degrades A␤ monomers but not oligomers or fibrils (31)(32)(33). IDE was added to a solution of A␤42 monomers, and this mixture was then added to subfractionated protofibril fractions (F1-F4) in supplemented 10ϫ DMEM (see under "Experimental Procedures").…”

Section: Separation Of Monomers From Protofibrils Retards A␤42 Fibrilmentioning

confidence: 99%

Aβ42 Neurotoxicity Is Mediated by Ongoing Nucleated Polymerization Process Rather than by Discrete Aβ42 Species

Jan¹,

Adolfsson

Allaman

et al. 2011

Journal of Biological Chemistry

166

160

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Aggregation of amyloid-␤ (A␤)2 peptides and deposition into neuritic plaques are hallmark features of Alzheimer disease (AD) neuropathology (1, 2). Therefore, research efforts during the past 3 decades have focused on elucidating the mechanisms of A␤ fibrillization, identifying toxic species, and developing strategies to inhibit and/or reverse A␤ amyloid formation and toxicity in vivo (3,4).A␤ peptides are produced as soluble monomers (5, 6) and undergo oligomerization and amyloid fibril formation via a nucleation-dependent polymerization process (7,8). During the course of in vitro A␤ fibril formation, various nonfibrillar aggregation intermediates, collectively called soluble oligomers or protofibrils, have been shown to precede the emergence of fibrils. Increasing evidence from various sources points to A␤ oligomers/protofibrils as putative toxic species in AD pathogenesis and suggests that these species are potential therapeutic targets for treating AD (reviewed in Refs. 9, 10). Although the toxic oligomer hypothesis has emerged as one of the major current working hypotheses in AD research, the development of effective diagnostic tools and therapies on the basis of this hypothesis has yet to be realized (11-13). This is partially due to the fact that identification of a single toxic A␤ species that correlates with AD progression and severity remains elusive. Furthermore, the exact mechanisms by which these species contribute to A␤ toxicity in vivo and the nature of the toxic species are not yet fully understood. Recent evidence suggests that accelerating the process of A␤ fibrillization greatly enhances A␤ toxicity in vitro (14) and the spread of amyloid pathology in vivo (15-17).Despite significant efforts by different groups to isolate specific intermediates along the amyloid formation pathway (12, 18 -22), the inherent heterogeneity of the process and metastable nature of A␤ oligomers (11-13) have precluded the isolation of a single toxic species. Unless covalently crosslinked (23), A␤ oligomers do not exist as stable entities, i.e. they evolve into higher order aggregates and, if they are onpathway intermediates, convert into fibrils (19). Therefore, it is plausible to assume that the structural dynamics of oligomers and factors that govern their interconversion and/or growth might influence some of the disease-related cytotoxic effects of A␤. In other words, an ongoing polymerization

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The AβCs of Aβ-cleaving Proteases

Cited by 76 publications

References 48 publications

Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer's disease

Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer's disease

Proteolytic Degradation of Amyloid -Protein

Aβ42 Neurotoxicity Is Mediated by Ongoing Nucleated Polymerization Process Rather than by Discrete Aβ42 Species

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