Nuclear Translocation Uncovers the Amyloid Peptide Aβ42 as a Regulator of Gene Transcription*

Barucker, Christian; Harmeier, Anja; Weiske, Joerg; Fauler, Beatrix; Albring, Kai Frederik; Prokop, Stefan; Hildebrand, Peter W.; Lurz, Rudi; Heppner, Frank L.; Huber, Otmar; Multhaup, Gerhard

doi:10.1074/jbc.m114.564690

Cited by 68 publications

(80 citation statements)

References 66 publications

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“…Although their potential roles in regulating gene expression are currently not well understood, significant progress is being made. For example, we have shown that the nuclear accumulation of A␤ peptides, other than A␤42, is independent from the recruitment on gene promoters (18). We found that A␤42 and A␤42G33A accumulate equally well in the nucleus, but only A␤42 can actively regulate gene expression.…”

Section: Possible Nuclear Functions Of Aicd A␤ and Taumentioning

confidence: 82%

“…These effects were specific for A␤42 and not detectable with peptides A␤43 and A␤38 or A␤42G33A, which is a substitution peptide known to form oligomeric ␤-pleated sheet complexes more readily than A␤42 WT peptide (90). Moreover, A␤42 had no effect on the expression of the Notch target HES1 (18). Although LRP1 and APP are similarly regulated as by AICD, KAI1 is downregulated by A␤42 and up-regulated by AICD.…”

Section: Possible Nuclear Functions Of Aicd A␤ and Taumentioning

confidence: 94%

“…Similarly to AICD, A␤42 has also been found to associate with regulatory elements of KAI1 and LRP1 within 30 min (after application) in ChIP experiments (18). Interestingly, Fe65 and histone acetyl transferase Tip60 were only detectable after 60 min, indicating that A␤42 translocated to the nucleus independent of Fe65 in contrast to AICD (59).…”

Section: Aicd A␤42 and Tau Interactions With Dnamentioning

confidence: 98%

“…Regarding A␤42, it appears that low-n oligomers (from dimers to octamers) of A␤42 peptides in the nucleus induce changes in gene transcription (18). At present, it is not clear whether A␤42 is binding at the KAI1 or LRP1 promoters or whether binding to DNA may affect DNA or chromatin structure (89).…”

Section: Possible Nuclear Functions Of Aicd A␤ and Taumentioning

confidence: 99%

“…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.…”

Section: Recently the Impact Of App Metabolites (App Intracellular Fmentioning

confidence: 99%

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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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Section: Possible Nuclear Functions Of Aicd A␤ and Taumentioning

confidence: 82%

Section: Possible Nuclear Functions Of Aicd A␤ and Taumentioning

confidence: 94%

Section: Aicd A␤42 and Tau Interactions With Dnamentioning

confidence: 98%

Section: Possible Nuclear Functions Of Aicd A␤ and Taumentioning

confidence: 99%

Section: Recently the Impact Of App Metabolites (App Intracellular Fmentioning

confidence: 99%

See 3 more Smart Citations

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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Alpha‐Synuclein Modulates the Physical Properties of DNA

Jiang

Rocha

Westling

et al. 2018

Chemistry A European J

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Fundamental research on Parkinson’s disease (PD) most often focuses on the ability of α-synuclein (aS) to form oligomers and amyloids, and how such species promote brain cell death. However, there are indications that aS also plays a gene-regulatory role in the cell nucleus. Here, the interaction between monomeric aS and DNA in vitro has been investigated with single-molecule techniques. Using a nanofluidic channel system, it was discovered that aS binds to DNA and by studying the DNA–protein complexes at different confinements we determined that aS binding increases the persistence length of DNA from 70 to 90 nm at high coverage. By atomic force microscopy it was revealed that at low protein-to-DNA ratio, the aS binding occurs as small protein clusters scattered along the DNA; at high protein-to-DNA ratio, the DNA is fully covered by protein. As DNA-aS interactions may play roles in PD, it is of importance to characterize biophysical properties of such complexes in detail.

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