Abstract
Aβ peptide that accumulates in Alzheimer’s disease brain, derives from proteolytic processing of the amyloid precursor protein (APP) that exists in three main isoforms derived by alternative splicing. The isoform APP695, lacking exons 7 and 8, is predominately expressed in neurons and abnormal neuronal splicing of APP has been observed in the brain of patients with Alzheimer’s disease. Herein, we demonstrate that expression of the neuronal members of the ELAVL protein family (nELAVLs) correlate with APP695 levels in vitro and in vivo. Moreover, we provide evidence that nELAVLs regulate the production of APP695; by using a series of reporters we show that concurrent binding of nELAVLs to sequences located both upstream and downstream of exon 7 is required for its skipping, whereas nELAVL-binding to a highly conserved U-rich sequence upstream of exon 8, is sufficient for its exclusion. Finally, we report that nELAVLs block APP exon 7 or 8 definition by reducing the binding of the essential splicing factor U2AF65, an effect facilitated by the concurrent binding of AUF-1. Our study provides new insights into the regulation of APP pre-mRNA processing, supports the role for nELAVLs as neuron-specific splicing regulators and reveals a novel function of AUF1 in alternative splicing.
Highlights
One of the hallmarks of Alzheimer’s disease (AD), the major cause of dementia in humans, is the abnormal deposition of aggregated amyloid-beta peptide (Αβ) in the brain[1]
Our analysis revealed a significant correlation of neuronal APP695 with neuronal ELAVL proteins (nELAVLs) (ELAVL2: Pearson r = 0.593, P < 0.05, ELAVL3: Pearson r =−0.510, P < 0.05, ELAVL4: Pearson r = 0.544, P < 0.05), but not with ELAV1, AUF-1 or TIA-1
There was no correlation between the levels of nELAVLs and APP770 or APP751 isoforms suggesting that in the human brain, nELAVL expression is correlated with APP695 expression
Summary
One of the hallmarks of Alzheimer’s disease (AD), the major cause of dementia in humans, is the abnormal deposition of aggregated amyloid-beta peptide (Αβ) in the brain[1]. It has been shown that APP695 is decreased, whereas APP770 is increased in the brain of AD patients[9,10,11,12] and abnormal neuronal splicing of APP pre-mRNA has been associated with aberrant Aβproduction[13,14]. Tissue specific AS is regulated by a subset of RNA-binding proteins (RBPs), namely splicing regulators, that interact with RNA motifs on their target pre-mRNAs and affect their processing. In the present study we provide evidence that nELAVLs are critically involved in the regulation of neuron-specific AS of both human and mouse APP pre-mRNA. We report that APP695 expression correlates with nELAVLs in the human brain and cell lines and most importantly demonstrate that nELAVs but not the ubiquitous ELAVL1, promote the exclusion of both exons 7 and 8 from the pre-mRNA to generate APP695. Our study provides new insights into a conserved neuronal mechanism for the regulation of APP695 expression and reveals a novel function of AUF-1 as an AS modulator
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