The physiology of the β‐amyloid precursor protein intracellular domain AICD

Background: Presenilin TMD8 contains a conserved AXXXAXXXG motif, involved in transmembrane protein interactions. Results: Mutation of PS AXXXAXXXG motifs strongly impacts ␥-secretase activity. Conclusion: The geometry and activity of ␥-secretase depend on the integrity of the conserved AXXXAXXXG motifs in TMD8. Significance: The PS AXXXAXXXG motif is a key determinant for understanding the structure, assembly, and function of the ␥-secretase complex.

Section: Discussionmentioning

confidence: 99%

“…The amyloidogenic C-terminal fragment generated by ␤-secretase (␤-CTF or C99) is processed by ␥-secretase at the ⑀-site, leading to the release of the APP intracellular domain (AICD) (1)(2)(3). The remaining A␤ fragment is further trimmed by ␥-secretase until the A␤ peptides of various lengths (A␤38 to A␤43) are released (4 -7).…”

Section: A␤mentioning

confidence: 99%

Presenilin Transmembrane Domain 8 Conserved AXXXAXXXG Motifs Are Required for the Activity of the γ-Secretase Complex

Marinangeli¹,

Tasiaux²,

Opsomer³

et al. 2015

“…sAPP␣) was not found to stimulate proliferation, this suggests that the APP intracellular domain (AICD) may be involved in mediating this effect. Indeed, based on an analogy with the notch intracellular domain (NICD), which is also released by ␥-secretase (39), a number of studies suggest that the AICD may regulate gene expression (40). Whether AICD regulates the expression of cystatin C is not yet known and will require further studies.…”

Section: Discussionmentioning

confidence: 99%

Role of Cystatin C in Amyloid Precursor Protein-induced Proliferation of Neural Stem/Progenitor Cells

Hu¹,

Hung²,

Cui

et al. 2013

Background:The role of the amyloid precursor protein (APP) in neural stem/progenitor cell (NSPC) proliferation is poorly understood. Results: Immunodepletion of cystatin C from NSPC conditioned medium abrogated an effect of APP on NSPC proliferation. Conclusion: Cystatin C mediates APP-induced NSPC proliferation. Significance: The results increase understanding of mechanisms promoting NSPC survival and differentiation.

“…Out of 70 ␥-secretase substrates, about 30 generate intracellular domains (ICD) with potential activity in transcriptional regulation (33), including AICD, which is mainly produced via the amyloidogenic pathway (34) and not released from plasma membrane-attached APP. The ␣-secretase-derived C-terminal stub C83 did not produce AICD (8).…”

Section: Possible Sources Of Nuclear Aicd A␤ and Taumentioning

confidence: 99%

“…does the central YENPTY motif of nuclear AICD directly interact with the phosphotyrosine-binding domain 2 (PBT2) of Fe65 (60); see review in Ref. 33). At present, the generally accepted view is that AICD could function as a transcription factor in the AFT complex.…”

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

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...