Abstract
A central event in Alzheimer’s disease is the accumulation of amyloid β (Aβ) peptides generated by the proteolytic cleavage of the amyloid precursor protein (APP). APP overexpression leads to increased Aβ generation and Alzheimer’s disease in humans and altered neuronal migration and increased long term depression in mice. Conversely, reduction of APP expression results in decreased Aβ levels in mice as well as impaired learning and memory and decreased numbers of dendritic spines. Together these findings indicate that therapeutic interventions that aim to restore APP and Aβ levels must do so within an ideal range. To better understand the effects of modulating APP levels, we explored the mechanisms regulating APP expression focusing on post-transcriptional regulation. Such regulation can be mediated by RNA regulatory elements such as guanine quadruplexes (G-quadruplexes), non-canonical structured RNA motifs that affect RNA stability and translation. Via a bioinformatics approach, we identified a candidate G-quadruplex within the APP mRNA in its 3’UTR (untranslated region) at residues 3008–3027 (NM_201414.2). This sequence exhibited characteristics of a parallel G-quadruplex structure as revealed by circular dichroism spectrophotometry. Further, as with other G-quadruplexes, the formation of this structure was dependent on the presence of potassium ions. This G-quadruplex has no apparent role in regulating transcription or mRNA stability as wild type and mutant constructs exhibited equivalent mRNA levels as determined by real time PCR. Instead, we demonstrate that this G-quadruplex negatively regulates APP protein expression using dual luciferase reporter and Western blot analysis. Taken together, our studies reveal post-transcriptional regulation by a 3’UTR G-quadruplex as a novel mechanism regulating APP expression.
Highlights
Amyloid plaques and neurofibrillary tangles are characteristic pathologic features of Alzheimer’s disease (AD), a progressive neurodegenerative disorder and the most common form of dementia [1]
Amyloid plaques are formed from the amyloid β peptide (Aβ), which is a proteolytic product of the amyloid precursor protein (APP)
Onset AD can arise from elevated Aβ levels due to altered APP processing caused by mutations in the γ-secretase genes PSEN1 or PSEN2 [2].The accumulation of Aβ peptides is thought to lead to tau hyperphosphorylation, which can result in synaptic dysfunction, neuronal death, and cognitive decline [14]
Summary
Amyloid plaques and neurofibrillary tangles are characteristic pathologic features of Alzheimer’s disease (AD), a progressive neurodegenerative disorder and the most common form of dementia [1]. Cleavage by α-secretase in the non-amyloidogenic pathway releases a secreted APP fragment (s-APP α) as well as a transmembrane α C-Terminal Fragment (CTF). Early-onset forms of AD arise from mutations leading to elevated Aβ production. Onset AD can arise from elevated Aβ levels due to altered APP processing caused by mutations in the γ-secretase genes PSEN1 or PSEN2 [2].The accumulation of Aβ peptides is thought to lead to tau hyperphosphorylation, which can result in synaptic dysfunction, neuronal death, and cognitive decline [14]. Elevated APP expression, and the associated increase in Aβ production via the amyloidogenic pathway, has deleterious effects on both neuronal and cognitive function
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