Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

Abstract

Amyloid precursor protein (APP) is a member of a gene family that includes two APP-like proteins, APLP1 and 2. Recently, it has been reported that APLP1 and 2 undergo presenilin-dependent c-secretase cleavage, as does APP, resulting in the release of an B6 kDa intracellular C-terminal domain (ICD), which can translocate into the nucleus. In this study, we demonstrate that the APLP2-ICDs interact with CP2/LSF/LBP1 (CP2) transcription factor in the nucleus and induce the expression of glycogen synthase kinase 3b (GSK-3b), which has broad-ranged substrates such as s-and b-catenin. The significance of this finding is substantiated by the in vivo evidence of the increase in the immunoreactivities for the nuclear C-terminal fragments of APLP2, and for GSK-3b in the AD patients' brain. Taken together, these results suggest that APLP2-ICDs contribute to the AD pathogenesis, by inducing GSK-3b expression through the interaction with CP2 transcription factor in the nucleus. The pathology of Alzheimer's disease (AD) is characterized by the deposition of neuritic plaques, of which the principal components are 40 and 42 amino-acid amyloid beta peptides (Ab) derived from amyloid precursor protein (APP). 1 APP belongs to a family of conserved type I transmembrane proteins including Apl-1 in Caenorhabditis elegans, 2 Appl in Drosophila, 3 and APP, 4 APP-like protein 1 (APLP1) 5 and APLP2 6,7 in mammals.APLP1 and 2 display substantial amino-acid and domain homologies with APP. Although they do not have an Ab domain, their intracellular C-terminal domains (ICDs) are highly similar to that of APP. 8 APLP1 is known to be implicated in synaptogenesis, 9,10 and recombinant APLP2 possesses an ability to promote neurite outgrowth. 11 However, their physiological roles in neurons are still not fully understood. In the brains of AD patients, APLP2 immunoreactivity has been detected in a subset of neuritic plaques, 12 suggesting that APLP2 might be involved in the pathogenesis of AD.APLP2 matures through the same secretory/cleavage pathway as APP 7 and previously, APLP1 and 2 were reported to be processed by g-secretase in a presenilin 1-dependent manner. 8,10 The APLP family can be also cleaved by esecretase to generate the ICD composed of the last 50 amino acids of APLPs C-terminus (C50). 13,14 Moreover, the ICDs of APLP1 and APLP2 produced by g-secretase enhanced Fe65-dependent gene transcriptional activation, as have been reported for the APP intracellular domain (AICD). 10 Fe65, which is known to be ones of the adaptor proteins for APP, contains three protein-protein interaction domains, a WW and two phosphotyrosine binding (PTB) domains. The PTB2 domain, which is located in the C-terminal half of the molecule, is responsible for the interaction between Fe65 and the cytosolic tail of APP through the YENPTY domain of APP. 15 Here, we demonstrate that the ICDs of APLP2 (APLP2-ICDs: C57, C50) interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase 3b (GSK-3b) expression, whereas their point mutants with...

Apoptosis in Alzheimer’s Disease: An Understanding of the Physiology, Pathology and Therapeutic Avenues

“…A neuronal cell model of apoptosis employing the phosphatidylinositol kinase-3 inhibitor LY294002, demonstrated that GSK 3 inhibition opens a new therapeutic avenue for AD [62].…”

“…Studies have also shown that AICD also interacts with p53 and augments its transcriptional activity and pro-apoptotic functions, thus emphasizing the role of AICD in p53-mediated apoptosis. AICD stimulated neuron-specific apoptosis is possibly regulated by glycogen synthase kinase-3b (GSK3b) and p53 [60,62]. Furthermore, the kinase c-AbI can modulate AICD-dependent cellular responses, instigating apoptosis and transcription of its target genes like neprilysin [60,63].…”

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“…Nrf2-regulating miR-153, whose expression is downregulated in APPswe/PSΔE9 AD murine model, directly targets APP and amyloid precursor-like protein 2 (APLP2) mRNAs binding their 3'-UTR [111]. APLP2 is a homologue of APP significantly upregulated in AD brains, and its C-terminal fragments contribute to the progression of the disease, decreasing cell survival [112]. Consistently, APP and APLP2 are downregulated in the brain of miR-153-transgenic mice with respect to wild type.…”

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“…18), but its detailed role in this process still needs further characterization. 19 The Upstream-binding protein 1 (UBP1) also known as the leaderbinding protein 1 (LBP1), is highly similar to TFCP2 with 88% sequence identity between human proteins. Similarly to TFCP2, its protein product is involved in the regulation of the alpha-globin gene in erythroid cells, and exhibits a highly specific tissue distribution.…”