Fe65 Stimulates Proteolytic Liberation of the β-Amyloid Precursor Protein Intracellular Domain

Abstract

The ␤-amyloid precursor protein (APP)-binding protein Fe65 is involved in APP nuclear signaling and several steps in APP proteolytic processing. In this study, we show that Fe65 stimulates ␥-secretase-mediated liberation of the APP intracellular domain (AICD). The mechanism of Fe65-mediated stimulation of AICD formation appears to be through enhanced production of the carboxyl-terminal fragment substrates of ␥-secretase and direct stimulation of processing by ␥-secretase. The stimulatory capacity of Fe65 is isoform-dependent, as the non-neuronal and a2 isoforms promote APP processing more effectively than the exon 9 inclusive neuronal form of Fe65. Intriguingly, Fe65 stimulation of AICD production appears to be inversely related to pathogenic ␤-amyloid production as the Fe65 isoforms profoundly stimulate AICD production and simultaneously decrease A␤42 production. Despite the capacity of Fe65 to stimulate ␥-secretase-mediated APP proteolysis, it does not rescue the loss of proteolytic function associated with the presenilin-1 familial Alzheimer disease mutations. These data suggest that Fe65 regulation of APP proteolysis may be integrally associated with its nuclear signaling function, as all antecedent proteolytic steps prior to release of Fe65 from the membrane are fostered by the APP-Fe65 interaction.

Synaptic NMDA Receptor Activation Stimulates α-Secretase Amyloid Precursor Protein Processing and Inhibits Amyloid-β Production

“…We also showed that coexpression of Fe65 negated the inhibitory effect of NMDA on AICD-Gal4-driven luciferase activity, and this may be explained by the recent finding that overexpression of Fe65 isoforms robustly stimulates AICD levels by increasing both the rate of ␣-CTF (C83) and ␤-CTF (C99) production and the rate of ␥-secretase-mediated cleavage of its immediate substrates (C83 and C99) (Wiley et al, 2007).…”

“…It has previously been reported that the AICD is a highly labile fragment that is stabilized when complexed with Fe65 (Kimberly et al, 2001); however, a more recent study has shown that overexpression of Fe65 stimulates both liberation of AICD from full-length APP and luciferase reporter gene transcription driven by an APP-Gal4VP16 fusion protein (Wiley et al, 2007). We examined whether Fe65 regulates APP695-Gal4-driven luciferase activity in primary cortical neurons and found that neurons cotransfected with plasmids encoding for APP695-Gal4 and Fe65 produced 15-20 times more luciferase activity than neurons transfected with APP695-Gal4 plasmid alone (Fig.…”

LINGO-1 promotes lysosomal degradation of amyloid-β protein precursor

“…Multiple AβPP-derived peptides are produced with varying length thereby affecting the reactivity with antibodies employed for immunoassay, and likely, varying the extractability from lysed cells. Consequently, we have employed a procedure that monitors γ-secretase mediated release of the intracellular domain (AICD) of AβPP, since release of Aβ peptides from AβPP by γ-secretase is accompanied by release of AICD (16,18). The methodology involves expression of AβPP modified by C-terminal fusion to a transcription factor, so that AICD release drives expression of a luciferase reporter gene.…”

FE65 regulates and interacts with the Bloom syndrome protein in dynamic nuclear spheres – potential relevance to Alzheimer's disease

“…Furthermore, FE65 and FE65L1 stimulate APP intracellular domain (AICD) generation (Chang et al, 2003;Wiley et al, 2007;Xie et al, 2007). However, the identification of several putative target genes have been controversially discussed (Baek et al, 2002;Bimonte et al, 2004;Müller et al, 2007;Telese et al, 2005;von Rotz et al, 2004).…”