Evidence That Aβ42 Plasma Levels in Presenilin-1 Mutation Carriers Do not Allow for Prediction of Their Clinical Phenotype

Jonghe, Chris De; Cras, Patrick; Vanderstichele, Hugo; Cruts, Marc; Vanderhoeven, Inge; Smouts, Iris; Vanmechelen, Eugeen; Martin, J. J.; Hendriks, Lydia; Broeckhoven, Christine Van

doi:10.1006/nbdi.1999.0247

Cited by 42 publications

(19 citation statements)

References 38 publications

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“…Among these mutations, the PS1 L166P mutation is of particular interest because it is associated with disease onset in adolescence. Moreover, the L166P mutation causes an exceptional increase in the A␤ 42 ͞ A␤ total ratio, similar to the FAD-associated PS1 G384A mutation (11,36). This extreme increase of A␤ 42 may be due to disruption of TM3 by the helix-breaking proline.…”

Section: Discussionmentioning

confidence: 91%

Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ ₄₂ production

Moehlmann

Winkler

Xia

et al. 2002

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

257

200

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Section: Discussionmentioning

confidence: 91%

Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ ₄₂ production

Moehlmann

Winkler

Xia

et al. 2002

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

257

200

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“…1C, Table 1). The catalytic motif mutant, mIAP G219A , adjacent to the aspartate in GxG 219 D, and the site of the familial Alzheimer disease (FAD) mutant G384A in presenilin (29,30), exhibits catalytic rates similar to mIAP Y161A (Table 1). Previous studies of the G384A presenilin variant (31) and corresponding variant in other SPP homologs (11,32) detected reduced end product via immunoblot.…”

Section: Resultsmentioning

confidence: 99%

Both positional and chemical variables control in vitro proteolytic cleavage of a presenilin ortholog

Naing

Kalyoncu

Smalley³

et al. 2018

Journal of Biological Chemistry

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Mechanistic details of intramembrane aspartyl protease (IAP) chemistry, which is central to many biological and pathogenic processes, remain largely obscure. Here, we investigated the in vitro kinetics of a microbial intramembrane aspartyl protease (mIAP) fortuitously acting on the renin substrate angiotensinogen and the C-terminal transmembrane segment of amyloid precursor protein (C100), which is cleaved by the presenilin subunit of γ-secretase, an Alzheimer disease (AD)-associated IAP. mIAP variants with substitutions in active-site and putative substrate gating residues generally exhibit impaired, but not abolished, activity toward angiotensinogen, and retain the predominant cleavage site (His-Thr). The aromatic ring, but not its hydroxyl substituent, in Tyr of the catalytic Tyr-Asp (YD) motif plays a catalytic role, and the hydrolysis reaction incorporates bulk water as in soluble aspartyl proteases. mIAP hydrolyzes the transmembrane region of C100 at two major presenilin cleavage sites, one corresponding to the AD-associated Aβ42 peptide (Ala-Thr) and the other the nonpathogenic Aβ48 (Thr-Leu). For the former site, we observed more favorable kinetics in lipid bilayer-mimicking bicelles than in detergent solution, indicating that substrate-lipid and substrate-enzyme interactions both contribute to catalytic rates. High-resolution MS analyses across four substrates support a preference for threonine at the scissile bond. However, results from threonine-scanning mutagenesis of angiotensinogen indicate a competing positional preference for cleavage. Our results indicate that IAP cleavage is controlled by both positional and chemical factors, opening up new avenues for selective IAP inhibition for therapeutic interventions. INTRODUCTIONIntramembrane proteases (IPs) cleave within a transmembrane (TM) helix of membranebound substrates to release cytoplasmic or extracellular proteins/peptides, which in turn translocate to different regions of the cell where they elicit their corresponding biological response related to, for example, cell differentiation, development, and metabolism (1). Despite their broad biomedical reach, basic questions surrounding the structure of the active enzyme, how substrates are presented, and how hydrolysis chemistry occurs in an active site sequestered within the hydrophobic lipid membrane, remain active areas of research.The least biochemically understood IP is the intramembrane aspartyl protease (IAP) enzyme class, one of just three bona fide IP types that hydrolyze substrates within the hydrophobic lipid environment by using different catalytic nucleophiles (2). IAPs employ membrane-

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“…However, the mechanism underlying the decrease in CSF-Aß 42 in dementia disorders is currently unclear and only tentative conclusions can be drawn as to the etiology. The fact that Aß 42 has been found in plasma [57] raises the question of the source of Aß 42 in the CSF. Furthermore, no study has hitherto investigated the CSF levels of Aß 42 premortem in AD cases that were diagnostically verified postmortem.…”

Section: Discussionmentioning

confidence: 99%

The Cerebrospinal Fluid Levels of Tau, Growth-Associated Protein-43 and Soluble Amyloid Precursor Protein Correlate in Alzheimer’s Disease, Reflecting a Common Pathophysiological Process

Sjögren

Davidsson

Gottfries

et al. 2001

Dement Geriatr Cogn Disord

Self Cite

109

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Cerebrospinal fluid (CSF) levels of tau (total tau), growth-associated protein-43 (GAP-43), soluble amyloid precursor protein (sAPP; i.e. total sAPP), and β-amyloid₄₂ (Aβ₄₂) were studied in patients with frontotemporal dementia (FTD; n = 14), Alzheimer’s disease (AD; n = 47) and vascular dementia (VAD; n = 16), and in age-matched controls (n = 12). CSF-tau was increased in AD compared to controls and FTD (p < 0.001 for both). CSF-GAP-43 was increased in AD compared to controls (p < 0.05), and both CSF-GAP-43 and CSF-sAPP were increased in AD compared to FTD (p < 0.01). Positive and highly significant correlations were found between CSF-tau and CSF-GAP-43 in all groups and between CSF-tau, CSF-GAP-43 and CSF-sAPP in AD. The correlations found may reflect a common pathophysiologic process such as axonal degeneration.

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Evidence That Aβ42 Plasma Levels in Presenilin-1 Mutation Carriers Do not Allow for Prediction of Their Clinical Phenotype

Cited by 42 publications

References 38 publications

Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ ₄₂ production

Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ ₄₂ production

Both positional and chemical variables control in vitro proteolytic cleavage of a presenilin ortholog

The Cerebrospinal Fluid Levels of Tau, Growth-Associated Protein-43 and Soluble Amyloid Precursor Protein Correlate in Alzheimer’s Disease, Reflecting a Common Pathophysiological Process

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Evidence That Aβ42 Plasma Levels in Presenilin-1 Mutation Carriers Do not Allow for Prediction of Their Clinical Phenotype

Cited by 42 publications

References 38 publications

Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ 42 production

Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ 42 production

Both positional and chemical variables control in vitro proteolytic cleavage of a presenilin ortholog

The Cerebrospinal Fluid Levels of Tau, Growth-Associated Protein-43 and Soluble Amyloid Precursor Protein Correlate in Alzheimer’s Disease, Reflecting a Common Pathophysiological Process

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Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ ₄₂ production

Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ ₄₂ production