β-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the 
transmembrane aspartyl protease that catalyzes the first cleavage step in the 
proteolysis of the APP to the amyloid β-protein (Aβ), a process involved in the 
pathogenesis of Alzheimer disease. BACE1 pre-mRNA undergoes complex alternative 
splicing, the regulation of which is not well understood. We identified a G-rich 
sequence within exon 3 of BACE1 involved in controlling splice site selection. 
Mutation of the G-rich sequence decreased use of the normal 5' splice site of 
exon 3, which leads to full-length and proteolytically active BACE1, and 
increased use of an alternative splice site, which leads to a shorter, 
essentially inactive isoform. Nuclease protection assays, nuclear magnetic 
resonance, and circular dichroism spectroscopy revealed that this sequence folds 
into a G-quadruplex structure. Several proteins were identified as capable of 
binding to the G-rich sequence, and one of these, heterogeneous nuclear 
ribonucleoprotein H, was found to regulate BACE1 exon 3 alternative splicing and 
in a manner dependent on the G-rich sequence. Knockdown of heterogeneous nuclear 
ribonucleoprotein H led to a decrease in the full-length BACE1 mRNA isoform as 
well as a decrease in Aβ production from APP, suggesting new possibilities for 
therapeutic approaches to Alzheimer's disease.