Functional activity of the novel Alzheimer's amyloid β-peptide interacting domain (AβID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis

Abstract

Amyloid β peptide (Aβ) plaque in the brain is the primary (post mortem) diagnostic criterion of Alzheimer’s disease (AD). Any physiological role of Aβ constituent is poorly understood. We have previously determined an Aβ interacting domain (AβID) in the promoters of AD–associated genes (Maloney and Lahiri, 2011). This AβID interacts in a DNA–sequence specific manner with Aβ. We now demonstrate novel Aβ activity as a possible transcription factor. Herein, we demonstrate Aβ–chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma (SK–N–SH) cells treated with FITC conjugated Aβ1–40 localized Aβ to the nucleus in the presence of H2O2–mediated oxidative stress. Furthermore, primary rat fetal cerebrocortical cultures were transfected with APP and BACE1 promoter–luciferase fusions, and rat PC12 cultures were transfected with polymorphic APP promoter–CAT fusion clones. Transfected cells were treated with different Aβ peptides and/or H2O2. Aβ treatment of cell cultures produced a DNA sequence–specific response in cells transfected with polymorphic APP clones. Our results suggest the Aβ peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD.

MicroRNA-339-5p Down-regulates Protein Expression of β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 (BACE1) in Human Primary Brain Cultures and Is Reduced in Brain Tissue Specimens of Alzheimer Disease Subjects

“…For A␤ assay, an equal volume of CM (25 l) was loaded onto a plate pre-coated with anti-human A␤ (35)(36)(37)(38)(39)(40) antibody (clone 1A10) and incubated overnight. This kit uses anti-human A␤ (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) as detection antibody. For A␤(1-42), 50 l of CM was loaded overnight onto an antibody pre-coated plate (anti-human A␤ 38 -42).…”

“…Several transcription factor sites have been validated in terms of physical interactions and functional effects. Sp1 (22), Yin Yang 1 (YY1) (25), NF-B (26), and possibly even A␤ itself (27,28) bind to the BACE1 promoter and regulate expression. Transcriptional regulation of BACE1 by p25/cdk5 leads to enhanced amyloidogenic processing (29).…”

Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease

“…A␤ has also been implicated as a transcription factor. In 2011, Lahiri and colleagues claimed the existence of a DNA sequence motif binding A␤ in the promoters of the A␤PP, BACE1, and APOE genes [150,151]. In 2012, Piccini et al [152] showed upregulation of BACE1 expression specifically by A␤ 42 (but not A␤ 40 ) applied to neuroblastoma cells apparently via the JNK signaling pathway and in 2014 Baracker et al [153] showed that cells can absorb A␤ and transport it into nuclei where, specifically, A␤ 42 (but not other isoforms) can form transcriptional complexes to repress expression of the genes LRP1 and KAI1.…”

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…Thus, this interplay might fuel a negative signaling loop with XBP1 reducing BACE1 and Aβ. Consequently, this further reduces BACE1 expression/activity, since Aβ has been shown to control BACE1 levels (42,(44)(45)(46). However, one cannot exclude alternative signaling pathways involving p25/CDK5 (47) or LRP1 (48,49).…”

“…Therefore, targeting mechanisms that could stabilize and protect or repair and reestablish neuronal contacts and at the same time reduce Aβ levels could be an optimal and efficacious strategy against AD pathology, as it was in an animal model (19). However, one should not overlook evidence that Aβ has many physiological functions through regulation of synaptic activity (for review, see (175)) and control of genes as a transcription factor (44,45,48). On this basis, XBP1 has the advantage of ameliorating neuronal plasticity and connectivity through both Aβ-dependent and -independent pathways, leading to an overall amelioration of memory function (19).…”