The β-Secretase Enzyme BACE in Health and Alzheimer's Disease: Regulation, Cell Biology, Function, and Therapeutic Potential

Abstract

The ␤-amyloid (A␤) peptide is the major constituent of amyloid plaques in Alzheimer's disease (AD) brain and is likely to play a central role in the pathogenesis of this devastating neurodegenerative disorder. The ␤-secretase, ␤-site amyloid precursor protein cleaving enzyme (BACE1; also called Asp2, memapsin 2), is the enzyme responsible for initiating A␤ generation. Thus, BACE is a prime drug target for the therapeutic inhibition of A␤ production in AD. Since its discovery 10 years ago, much has been learned about BACE. This review summarizes BACE properties, describes BACE translation dysregulation in AD, and discusses BACE physiological functions in sodium current, synaptic transmission, myelination, and schizophrenia. The therapeutic potential of BACE will also be considered. This is a summary of topics covered at a symposium held at the 39th annual meeting of the Society for Neuroscience and is not meant to be a comprehensive review of BACE.BACE: the ␤-secretase in Alzheimer's disease Although the etiology of Alzheimer's disease (AD) is not completely understood, the study of disease genes that cause AD has revealed important clues about the pathogenesis of this disorder. Familial AD (FAD) cases are caused by autosomal dominant mutations in the genes for amyloid precursor protein (APP) and the presenilins (PS1 and PS2) (Sisodia and St George-Hyslop, 2002). These mutations increase production of the 42-aa-long, fibrillogenic form of A␤ (A␤ 42 ), relative to A␤ 40 . In addition, patients with APP gene duplications or individuals with Down's syndrome (trisomy 21), who have increased dosage of the APP gene (located on chromosome 21), develop early-onset AD and overproduce A␤ 42 (Hardy, 2006). These findings, along with a large body of evidence from other sources (Selkoe, 2008), strongly suggest that A␤ 42 plays a central, early role in AD pathogenesis. Thus, therapeutic strategies to lower cerebral A␤ 42 levels are expected to be beneficial for the treatment or prevention of AD.A␤ is produced through the endoproteolysis of APP, a large type 1 transmembrane protein. Cleavage of APP by two proteases, the ␤-and ␥-secretases, is required to liberate A␤ from APP (Tanzi and Bertram, 2005). The ␤-secretase cuts APP first to generate the N terminus of A␤, thus producing a membrane bound C-terminal fragment called C99. Then, ␥-secretase cleaves C99 to release the mature A␤ peptide. A third protease, ␣-secretase, cuts APP within the A␤ domain, thus precluding A␤ formation.

Increased Expression of Reticulon 3 in Neurons Leads to Reduced Axonal Transport of β Site Amyloid Precursor Protein-cleaving Enzyme 1

“…The cellular localization of BACE1 in established cell lines has been investigated extensively (13). However, its localization in primary neurons is less well described because of limitations in the detection of endogenous BACE1 by commercially available antibodies.…”

“…The cellular trafficking of BACE1 is regulated by various proteins such as adaptor complexes and retromers (13)(14)(15). For example, increased levels of sortilin, a Vps10p domain-sorting receptor, enhances the retrograde transport of BACE1 from endosomes to the TGN (16).…”

Ca2+ Influx through Store-operated Ca2+ Channels Reduces Alzheimer Disease β-Amyloid Peptide Secretion

“…In the A␤-producing amyloidogenic pathway, APP is first cleaved by the aspartyl protease ␤-secretase (␤-site APP-cleaving enzyme (BACE1)) within its extracellular domain, liberating the soluble ectodomain sAPP␤ and generating a membrane-tethered ␤-C-terminal fragment (␤-CTF) (6). The ␤-CTF is then cleaved within its transmembrane domain by ␥-secretase, releasing A␤ and the cytoplasmic APP intracellular domain (AICD).…”

ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1

“…β -site amyloid precursor protein cleaving enzyme 1 (BACE1) is the major β-secretase, and therefore the key rate-limiting factor in the production of amyloid β (Aβ) in Alzheimer's disease (AD) (1). BACE1 is a single-membrane spanning protease synthesized in the endoplasmic reticulum and posttranslationally modified by N-glycosylation and furin-processing in the Golgi apparatus.…”