Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

Dimitrov, Milen; Alattia, Jean René; Lemmin, Thomas; Lehal, Rajwinder; Fligier, Andrzej; Houacine, Jemila; Hussain, Ishrut; Radtke, Freddy; Peraro, Matteo Dal; Beher, Dirk; Fraering, Patrick C.

doi:10.1038/ncomms3246

Cited by 82 publications

(107 citation statements)

References 43 publications

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“…Such increased accessibility of T48 for ε-cleavage will lead to enhanced ε-cleavage at T48 relative to T49. This has been recently demonstrated by Dimitrov et al , who reported a dramatic enhancement in the ratio of AICD49-99/AICD50-99 in V44A and other FAD mutants near the γ -secretase cleavage site 34 . The proposed mechanistic hypothesis is also consistent with the report that FAD mutations within APP usually increase the Aβ42/Aβ40 ratio by modifying the product line preference of γ -secretase 35 .…”

Section: Discussionsupporting

confidence: 58%

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Familial Alzheimer’s mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site

et al. 2014

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The high Aβ42/Aβ40 production ratio is a hallmark of familial Alzheimer’s disease, which can be caused by mutations in the amyloid precursor protein (APP). The C-terminus of Aβ is generated by γ-secretase cleavage within the transmembrane domain of APP (APPTM), a process that is primed by an initial ε-cleavage at either T48 or L49, resulting in subsequent production of Aβ42 or Aβ40, respectively. Here we solve the dimer structures of wild-type APPTM (AAPTM WT) and mutant APPTM (FAD mutants V44M) with solution NMR. The right-handed APPTM helical dimer is mediated by GXXXA motif. From the NMR structural and dynamic data, we show that the V44M and V44A mutations can selectively expose the T48 site by weakening helical hydrogen bonds and increasing hydrogen–deuterium exchange rate (kex). We propose a structural model in which FAD mutations (V44M and V44A) can open the T48 site γ-secretase for the initial ε-cleavage, and consequently shift cleavage preference towards Aβ42.

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Section: Discussionsupporting

confidence: 58%

“…Indeed, it has been reported recently that V44A dramatically increase the ratio of AICD49-99/AICD50-99 (ref. 34), where AICD49-99 and AICD50-99 are the product of ε-cleavage at L48 and T49, respectively.…”

Section: Resultsmentioning

confidence: 99%

Familial Alzheimer’s mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site

et al. 2014

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“…The remaining membrane bound APP fragment, C99, is processed by multiple g-secretase cleavages. The first occurs at the cleavage site epsilon (ε-site, Figure 1B) to produce the AICD and then, after g-secretase cleavages trim the membrane bound producing Ab species that differ in protein length including Ab38, Ab40 (most common fragment), Ab42 (self-aggregative fragment), and Ab43 [93]. Genetic mutations in APP are located in or near the Ab sequence and in the proximity of the cleavage sites of the secretases (Fig.…”

Section: The Amyloid Cascadementioning

confidence: 97%

“…2A and 2B). The mutations are predicted to cause AD through aberrant APP processing determining either increased Ab levels or increased production of Ab42 (and Ab43) peptide over Ab40, triggering Ab aggregation [93]. From its postulation, the "amyloid cascade hypothesis" has been supported and questioned (as reviewed by Morris et al [94]) acknowledging that Ab has an important role in AD pathogenesis although its role in the disease process is most likely much more multifaceted.…”

Section: The Amyloid Cascadementioning

confidence: 98%

Molecular genetics of early‐onset Alzheimer's disease revisited

Cacace

Sleegers

Broeckhoven

2016

Alzheimer's & Dementia

435

361

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As the discovery of the Alzheimer's disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a apolipoprotein E (APOE) risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries.

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“…The N-terminal half of the TMS of APP is stabilized the GXXXG interaction motif with Gly-29 and Gly-33 (in red) as the central residues (51,96,97). In addition to familial mutations (98), e.g. T43I (11), TMS interactions affect the ⑀-cut exerted by the ␥-secretase and shift the ratio of the two AICD species between the A␤42 (AICD 49 -99) and the A␤40 product line (AICD 50 -99).…”

Section: Aicd A␤42 and Tau Interactions With Dnamentioning

confidence: 99%

Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

Multhaup

Huber

Buée

et al. 2015

Journal of Biological Chemistry

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Alzheimer disease (AD) 2 is the most common form of dementia and a leading cause of death. Amyloid-␤ (A␤) peptides of varying length (30 -51 amino acid residues) are produced by the sequential, proteolytic processing of the amyloid precursor protein (APP) by ␤-and ␥-secretases (1, 2). In the healthy brain, these protein fragments are normally degraded and eliminated. In the AD brain, the 42-amino acid peptide (A␤42) is prone to form aggregated amyloid oligomers, which are believed to contribute to plaque formation and cognitive decline (3-6).The ␥-secretase also liberates an intracellular fragment called AICD composed of up to 50 residues depending on N-terminal variations (7-9). The first identification of the APP intracellular fragment (AICD) and its detection in brain tissue (8) immediately suggested that it has transcriptional activity, like the Notch intracellular domain (NICD). Whether amyloid A␤ represents a biologically inert bypass product of APP processing or can harbor its own function is a leading question in the AD field. A␤ is potentially toxic depending on its biophysical state (10). Equimolar amounts of the A␤ peptides and the C-terminal fragment AICD are derived from the ␤-C-terminal fragment C99 (11), which represents the APP fragment generated by the initial APP cleavage by ␤-secretase (Fig. 1).A seminal discovery concerning the transcriptional regulatory function of the APP cytoplasmic tail was the observation of its complex formation with Fe65 and the histone acetyltransferase Tip60 and transcriptional activity in reporter gene assays (12). Transactivation of transcription requires ␥-secretase activity and nuclear translocation of Fe65 but not of AICD under these assay conditions (13). However, other studies detected AICD in transcriptional complexes on promoters of target genes using ChIP (see below).In addition, there is evidence that soluble APP fragments (sAPP) of the ectodomain can modulate gene transcription in stimulating downstream signaling through unknown sAPP receptor(s) (14). Accumulation of intracellular A␤ species in neuronal cells before plaque formation leading to concomitant loss of MAP2 expression suggested that A␤ may affect expression or turnover of other proteins (15-17). However, it was not clarified whether this occurs at the transcriptional or translational level.Using a variety of techniques, the recently detected uptake of A␤ peptides into the nuclei of cultured cells (as well as in vivo) revealed that A␤42 possesses unique modulatory activity (18). Direct evidence for the presence of (i) nuclear A␤42 in wildtype animals, (ii) the increased level of nuclear A␤42 in APPoverexpressing animals, and (iii) the detection of nuclear A␤ in quantities comparable with other transcription factors imply a certain biological relevance.The second major hallmark of AD pathology is the presence of neurofibrillary tangles and is associated with intracellular Tau aggregates called neurofibrillary tangles and with modified Tau (19). Although the neuronal Tau (tubulin-associated unit...

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Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

Cited by 82 publications

References 43 publications

Familial Alzheimer’s mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site

Familial Alzheimer’s mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site

Molecular genetics of early‐onset Alzheimer's disease revisited

Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

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