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Abbravation: EMBO Molecular Medicine

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EMBO Press

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10.1007/pl00001233

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1757-4684

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A new way APP mismetabolism can lead to Alzheimer

Authors: John Hardy Rita Guerreiro
Publish Date: 2011/05/05
Volume: 3, Issue: 5, Pages: 247-248
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Abstract

Amyloid precursor protein APP is a transmembrane protein which is sequentially cleaved at several sites by different enzymes Cleavage leads to the production of different Aβ β amyloid species which—when overproduced and aggregated—are a major cause of Alzheimers diseaseThe main cleavage sites in APP are the β‐ and γ/ε‐sites mediated by the respective secretases Fig 1 Importantly mutations in APP and the presenilins have been shown to cause Alzheimers disease by a remarkable number of mechanisms Now it seems there is one at a previously underestimated sitePathogenic mutations in APP Amino acids highlighted in red are known to be pathogenic The newly discovered mutation affecting cleavage at the β′‐site is highlighted in grey Cleavage sites for different secretases are indicated Note that the γ‐secretase cleaves APP at multiple sites starting between amino acid 718 and 719 and then proceeding towards 709 and 710 Modified from http//wwwalzforumorg/res/com/mut/app/diagram1asp courtesy of Richard Crook and the Alzheimer Research ForumAPP gene duplications and Down syndrome seem to simply cause more flux through the processing pathway by APP gene dose Rovelet‐Lecrux et al 2006 the London series of mutations and presenilin mutations increase the proportion of long Aβ species by marginally altering the production from the γ‐secretase cleavage Scheuner et al 1996 and the Flemish and similar Alzheimer causing mutations appear to reduce flux through the competing α‐secretase pathway De Jonghe et al 1998 Perhaps most famously the Swedish mutation increased the flux through the β pathway and produced more Aβ beginning at residue 1 of Aβ APP residue 672 In one of the most elegant experiments in the Alzheimer literature Citron and colleagues Citron et al 1995 showed by exhaustive mutagenesis that only the Swedish mutation M671L was a better substrate for β‐secretase cutting at this site this specificity is one of the most powerful arguments for the amyloid hypothesis of the disease Hardy Selkoe 2002 However the β‐secretase cleavage of APP is more complicated than simply cutting between residues 671 and 672 yielding peptides beginning with D672 since there is an alternative β cleavage named β′ between residue 681 and 682 positions 10 and 11 of the Aβ sequence Yang et al 2004 This cleavage generates an alternative series of Aβ molecules beginning at E682 position 12 of AβRemarkably in this issue of EMBO Molecular Medicine Zhou et al 2010 report a mutation APP E682K occurring in a case of early onset Alzheimers disease which disrupts this β′ cleavage and which like the Swedish mutation leads to more cleavage between residues 671 and 672 and thus more full‐length Aβ This is potentially important because it shows that these two cleavage sites are genuine alternatives to each other and implies that the peptides starting at position 11 are significantly less amyloidogenic than those starting at position 1 Clearly it also implies that if we could modulate β‐secretase cleavage towards the β′‐site it would have potential therapeutic benefit if we could modulate β‐secretase cleavage towards the β′‐site it would have potential therapeutic benefit although it is not obvious how this might be achievedThese interesting results and interpretations are subject to a caveat however that we cannot be sure that the mutation was genuinely pathogenic Genetic causation can only be proven by either linkage segregation within a family or association more frequent occurrence in affected individuals than in controls In this case the mutation has only been found in a single individual and so neither the criteria for linkage nor association have been met However clearly we now know something of the biology of autosomal dominant Alzheimers disease initiation and it is therefore tempting and to some extent appropriate to assign pathogenicity based on the relevant biology of the mutation We have suggested a formal process for this assessment in the regard to APP and presenilin mutations Guerreiro et al 2010 and under this system this variant APP E682K would be assigned ‘possible’ pathogenic mutation status As the authors briefly discuss the problems in assigning pathogenic status even to APP variants in Alzheimers disease are real assigning pathogenic status to variants in a genome wide fashion will clearly be extremely difficult


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citation journal title=EMBO Mol Medcitation author=L Zhoucitation year=2011citation pmid=21500352citation doi=101002/emmm201100138


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