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Regulation of APP processing and Aβ production by BACE1

University of British Columbia

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease among elderly people. The main symptoms of AD are memory loss and cognitive deficits. One of the hallmarks of AD is neuritic plaques in the brain. Amyloid β protein (Aβ), a peptide of 39–42 amino acids, forms the predominant component of plaques. Aβ is generated from amyloid-β precursor protein (APP) by sequential cleavages mediated by β-secretase and γ-secretase. Previous studies have shown that BACE1 can cleave APP at the ASP+¹ site or at the Glu+¹¹ site of Aβ domain. Cleavage at ASP+¹ is required for generating full length Aβ and increases in cleavage at ASP+¹ site has been considered as one of the major pathological pathways in AD cases. Swedish mutant APP, carrying double mutations (Lys⁵⁹⁵-Met⁵⁹⁶ to Asn⁵⁹⁵-Leu⁵⁹⁶) close to the ASP+¹ site in APP gene, causes early onset of familial AD. The Swedish mutation increases BACE1 cleavage at ASP+¹ site, resulting in significant increase of Aβ production. However, how BACE1 regulates APP processing at ASP+¹ and Glu+¹¹ remains elusive. Our preliminary studies indicated that majority of wild type APP is cleaved by BACE1 at Glu+¹¹ site, in contrast, Swedish mutation shifts the major cleavage site from Glu+¹¹ to ASP+¹ , resulting in significant increase of Aβ production under pathological condition. This work provides new insights in the pathological pathway of AD and suggests a major potential for the pharmaceutical development.

Text

2011-04-13

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/33601

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/