The beta-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential

Abstract

The beta-amyloid (Abeta) 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 beta-secretase, beta-site amyloid precursor protein cleaving enzyme (BACE1; also called Asp2, memapsin 2), is the enzyme responsible for initiating Abeta generation. Thus, BACE is a prime drug target for the therapeutic inhibition of Abeta 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.

Figure 1.

The structural organization of BACE1. Each predicted domain is represented by a colored rectangle with corresponding amino acid numbers shown below. D₉₂TG and D₂₉₈SG are the active site aspartic acid motifs and together they compose the catalytic domain of BACE1. SP, Pro, TM, and C represent signal peptide, propeptide, transmembrane, and C-terminal domains, respectively. Glycosylation and phosphorylation sites are indicated by Ns and S, respectively. Three disulfide bonds (SS) are also depicted connecting amino acids 216–420, 278–443, and 330–380. S-palmitoylation occurs at Cys⁴⁷⁴, Cys⁴⁷⁸, Cys⁴⁸², and Cys⁴⁸⁵. Finally, a disintegrin and metalloprotease (ADAM)-like sheddase cleaves BACE1 between Ala⁴²⁹ and Val⁴³⁰ (arrow) to allow BACE1 ectodomain secretion.

Figure 2.

BACE1 substrate processing in the cell. The major known BACE1 substrates are depicted as colored stick figures in the membrane: APP, APLP2, APLP2, IL-1R2, LRP, Na_vβ2, NRG1, PSGL-1, and ST6Gal1. Cleavage of APP by BACE1 (←β) in the endosome is shown as a typical example of BACE1 substrate processing. Most, if not all, BACE1 substrates are also processed by γ-secretase (←γ), which in the case of APP releases Aβ (red rectangle) for secretion. APP intracellular domain (AICD) is also released and acts as a cotransactivator of gene transcription in the nucleus, similar to the function of Na_vβ2 intracellular domain (β2ICD) in Na_v1α gene expression. Type III NRG1 is cleaved by BACE1 at a site adjacent to the transmembrane domain (β→). The second cut may occur by either BACE1 or ADAM cleavage (B/A→) and will release an EGF-like domain (blue rectangle) that signals through ErbB4 in adjacent glial cells to regulate axon myelination. Type I NRG1 and NRG3 are also cleavable by BACE1. ST6Gal1 is processed by BACE1 in the trans-Golgi network. PS1, Presenilin-1 component of γ-secretase; N and C, N terminus and C terminus of NRG1, respectively.