Generation of an Apoptotic Intracellular Peptide by γ-Secretase Cleavage of Alzheimer's Amyloid ß Protein Precursor

Abstract

The amyloid β protein precursor (AβPP) is sequentially processed by β-and γ-secretases to generate the Aβ peptide. The biochemical * B.P. and L.P. have equally contributed to this work.

JNK-interacting protein-1 promotes transcription of Aβ protein precursor but not Aβ precursor-like proteins, mechanistically different than Fe65

“…There has also been much interest recently in another peptide derived from A␤PP, the A␤PP intracellular domain (AID) fragment, which extends from the ␥-secretase cleavage site to the carboxyl terminal of A␤PP. The AID peptide was initially overlooked probably because it is very unstable and difficult to detect (6,7), and it was overshadowed by the A␤ fragment, which has been at the center of AD theory. The AID peptide was first identified in the brains of patients with AD and was shown to either sensitize or induce cells to undergo apoptosis (6).…”

The γ-secretase-generated intracellular domain of β-amyloid precursor protein binds Numb and inhibits Notch signaling

“…APP normally undergoes a series of endoproteolytic cleavages: twice within the extracellular domain (␣-and ␤-sites), mediated by tumor necrosis factor-converting enzyme and ␤APP-cleaving enzyme, respectively, and once within the transmembrane domain (␥-site) (1)(2)(3)(4). The cleavage of APP by the Presenilin-dependent ␥-secretase liberates amyloid-␤ (A␤) peptides (2)(3)(4) and the APP intracellular domain (AID) (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Two A␤ species of either 42 or 40 residues (A␤42 and A␤40) are the major component of amyloid plaques in the brain of AD patients (1,2).…”

“…Two A␤ species of either 42 or 40 residues (A␤42 and A␤40) are the major component of amyloid plaques in the brain of AD patients (1,2). The corresponding AID peptides of either 57 or 59 aa have been detected only recently in human brain (5), likely because they are rapidly degraded (11). Although the biological function of APP is unclear, recent data indicate that AID can lower the cellular threshold to apoptosis (5,10).…”

“…The corresponding AID peptides of either 57 or 59 aa have been detected only recently in human brain (5), likely because they are rapidly degraded (11). Although the biological function of APP is unclear, recent data indicate that AID can lower the cellular threshold to apoptosis (5,10). Furthermore, AID was recently shown to form a multimeric complex with the nuclear adaptor protein Fe65 and the histone acetyltransferase Tip60, which possesses potent transcriptional activity (13).…”

Regulation of gene expression by the amyloid precursor protein: inhibition of the JNK/c-Jun pathway

“…5,6 However, at present, little is known about the biological function of the APP C-terminal region from which the APP intracellular domain (AICD) is cleaved off by g-secretase. 2,7 Recent findings indicate that AICD may serve as a membrane-to-nucleus messenger; 8,9 thus, both sAPPa and AICD might link APP to regulation of transcriptional processes. The YENPTY motif of the C-terminal domain of APP has been shown to bind to several interaction partners, among them Fe65 and c-Jun N-terminal kinase (JNK)-interacting protein-1b (JIP-1b).…”