Analysis of peripheral amyloid precursor protein in Angelman Syndrome

Abstract

Angelman Syndrome is a rare neurodevelopmental disorder associated with significant developmental and communication delays, high risk for epilepsy, motor dysfunction, and a characteristic behavioral profile. While Angelman Syndrome is known to be associated with the loss of maternal expression of the ubiquitin-protein ligase E3A gene, the molecular sequelae of this loss remain to be fully understood. Amyloid precursor protein (APP) is involved in neuronal development and APP dysregulation has been implicated in the pathophysiology of other developmental disorders including fragile X syndrome and idiopathic autism. APP dysregulation has been noted in preclinical model of chromosome 15q13 duplication, a disorder whose genetic abnormality results in duplication of the region that is epigenetically silenced in Angelman Syndrome. In this duplication model, APP levels have been shown to be significantly reduced leading to the hypothesis that enhanced ubiquitin-protein ligase E3A expression may be associated with this phenomena. We tested the hypothesis that ubiquitin-protein ligase E3A regulates APP protein levels by comparing peripheral APP and APP derivative levels in humans with Angelman Syndrome to those with neurotypical development. We report that APP total, APP alpha (sAPPα) and A Beta 40 and 42 are elevated in the plasma of humans with Angelman Syndrome compared to neurotypical matched human samples. Additionally, we found that elevations in APP total and sAPPα correlated positively with peripheral brain derived neurotrophic factor levels previously reported in this same patient cohort. Our pilot report on APP protein levels in Angelman Syndrome warrants additional exploration and may provide a molecular target of treatment for the disorder. © 2016 Wiley Periodicals, Inc.

Angelman syndrome: Current and emerging therapies in 2016

“…In a pilot study of 11 children and adults with AS, it was found that the plasma concentrations of amyloid precursor protein (APP) and its breakdown products were higher in those with AS compared to age‐ and gender‐matched controls, and the levels of total APP and APP alpha were positively correlated with plasma BDNF concentrations, but the levels of total APP and its breakdown products did not correlate with the two neurodevelopmental outcome measures that were used in the study [Erickson et al, ]. The clinical implications of these findings remain unclear, but the authors suggested that APP (or its breakdown products) might be a therapeutic target in the future.…”

Dysfunction of the ubiquitin ligase E3A Ube3A/E6-AP contributes to synaptic pathology in Alzheimer’s disease

“…There is solid evidence for this idea. First, AS patients have significantly elevated plasma Aβ40 and 42 compared to age-matched control individuals 62 . Second, aberrant APP regulation has been reported in models of chromosome 15q11–13 duplication, in which Ube3A gene expression is increased 1.5- to 2-fold, which demonstrated that APP levels were decreased 10-fold relative to control samples 63 .…”

Eye gaze and pupillary response in Angelman syndrome

“…Seventeen individuals with a confirmed genetic diagnosis of AS were recruited at Indiana School of Medicine and Cincinnati Children's Hospital by the same investigators (CAE, EVP, LKW) between 2012 and 2015 as part of an ongoing effort to evaluate the neurobehavioral and molecular phenotype of AS (Erickson et al, 2016;Wink et al, 2015). AS subjects were characterized as UBE3A deletion or non-deletion genotype according to clinical diagnostic sequencing of the UBE3A gene.…”