Mutations in the gene encoding the amyloid protein precursor (APP) cause autosomal dominant Alzheimer's disease. Cleavage of APP by unidentified proteases, referred to as beta- and gamma-secretases, generates the amyloid beta-peptide, the main component of the amyloid plaques found in Alzheimer's disease patients. The disease-causing mutations flank the protease cleavage sites in APP and facilitate its cleavage. Here we identify a new membrane-bound aspartyl protease (Asp2) with beta-secretase activity. The Asp2 gene is expressed widely in brain and other tissues. Decreasing the expression of Asp2 in cells reduces amyloid beta-peptide production and blocks the accumulation of the carboxy-terminal APP fragment that is created by beta-secretase cleavage. Solubilized Asp2 protein cleaves a synthetic APP peptide substrate at the beta-secretase site, and the rate of cleavage is increased tenfold by a mutation associated with early-onset Alzheimer's disease in Sweden. Thus, Asp2 is a new protein target for drugs that are designed to block the production of amyloid beta-peptide peptide and the consequent formation of amyloid plaque in Alzheimer's disease.

Bace1 is an endopeptidase that cleaves the amyloid precursor protein at the beta-secretase site. Apart from this cleavage, the functional importance of Bace1 in other physiological events is unknown. We show here that Bace1 regulates the process of myelination and myelin sheath thickness in the central and peripheral nerves. In Bace1-null mice, the process of myelination was delayed and myelin thickness was markedly reduced, indicating that genetic deletion of Bace1 causes hypomyelination. Bace1-null mice also showed altered neurological behaviors such as elevated pain sensitivity and reduced grip strength. Further mechanistic studies showed an altered neuregulin-Akt signaling pathway in Bace1-null mice. Full-length neuregulin-1 was increased and its cleavage product was decreased in the CNS of Bace1-null mice. Furthermore, phosphorylated Akt was also reduced. Based upon these and previous studies, we postulate that neuronally enriched Bace1 cleaves neuregulin-1 and that processed neuregulin-1 regulates myelination by means of phosphorylation of Akt in myelin-forming cells.

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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.

The β secretase, widely known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), initiates the production of the toxic amyloid β (Aβ) that plays a crucial early part in Alzheimer’s disease pathogenesis. BACE1 is a prime therapeutic target for lowering cerebral Aβ concentrations in Alzheimer’s disease, and clinical development of BACE1 inhibitors is being intensely pursued. Although BACE1 inhibitor drug development has proven challenging, several promising BACE1 inhibitors have recently entered human clinical trials. The safety and efficacy of these drugs are being tested at present in healthy individuals and patients with Alzheimer’s disease, and will soon be tested in individuals with presymptomatic Alzheimer’s disease. Although hopes are high that BACE1 inhibitors might be efficacious for the prevention or treatment of Alzheimer’s disease, concerns have been raised about potential mechanism-based side-effects of these drugs. The potential of therapeutic BACE1 inhibition might prove to be a watershed in the treatment of Alzheimer’s disease.

Whether elevated ␤-secretase (BACE) activity is related to plaque formation or amyloid ␤ peptide (A␤) production in Alzheimer's disease (AD) brains remains inconclusive. Here, we report that we used sandwich enzyme-linked immunoabsorbent assay to quantitate various A␤ species in the frontal cortex of AD brains homogenized in 70% formic acid. We found that most of the A␤ species detected in rapidly autopsied brains (<3 h) with sporadic AD were A␤ 1-x and A␤ 1-42, as well as A␤x-42. To establish a linkage between A␤ levels and BACE, we examined BACE protein, mRNA expression and enzymatic activity in the same brain region of AD brains. We found that both BACE mRNA and protein expression is elevated in vivo in the frontal cortex. The elevation of BACE enzymatic activity in AD is correlated with brain A␤ 1-x and A␤1-42 production. To examine whether BACE elevation was due to mutations in the BACE-coding region, we sequenced the entire ORF region of the BACE gene in these same AD and nondemented patients and performed allelic association analysis. We found no mutations in the ORF of the BACE gene. Moreover, we found few changes of BACE protein and mRNA levels in Swedish mutated amyloid precursor protein-transfected cells. These findings demonstrate correlation between A␤ loads and BACE elevation and also suggest that as a consequence, BACE elevation may lead to increased A␤ production and enhanced deposition of amyloid plaques in sporadic AD patients. A lzheimer's disease (AD) is the most common cause of dementia in the population Ͼ60 years of age. Senile plaques and paired helical filaments are the two hallmarks of the brain pathology of AD (1-3). Amyloid ␤ peptide (A␤), a major protein component (4 kDa) of the senile plaque (4), is generated from amyloid precursor protein (APP) by enzymatic digestion involving ␤-secretase (BACE) and ␥-secretase activities.The mechanisms of A␤ accumulation in the majority of AD patients (sporadic AD) remain unclear although a minority of AD patients carry mutations in the APP and presenilin (PS) genes, which lead to an increase in A␤ production (5). A␤ is the cleavage product from APP by two enzymes: BACE and ␥-secretase. BACE is a transmembrane aspartyl protease and has recently been cloned and characterized (6-10). Overexpression of BACE in transfected cells increases the amount of C99 and C89, which are both BACE-cleavage products. More BACE-cleaved APP products were found in the Swedish mutation (APPsw) as compared with that in wild-type substrate (APPwt) (6). The BACE cleavage occurs at the known ␤-cleavage sites of APP, Asp 1, and Glu 11 (6-10). The role of BACE played in A␤ production in vitro might explain the higher production of A␤ peptide in AD brains and the early onset of Swedish familial AD. Recently, we and other investigators demonstrated higher BACE expression levels found in sporadic AD brains compared with healthy age-matched controls (11-13). A␤ accumulation in the AD brain is a chronic process and a small elevation of BACE might lead to a significant increase in ...

A Drosophila Stat gene (D-Stat) with a zygotic segmental expression pattern was identified. This protein becomes phosphorylated on Tyr-704 when coexpressed in Schneider cells with a Drosophila janus kinase (JAK), Hopscotch (HOP). The phosphorylated protein binds specifically to the consensus sequence TTCCCGGAA. Suppressor mutations of hopTum-I, a dominant hyperactive allele of hop whose phenotype is hematocyte overproduction and tumor formation, were selected. One of these mutants, statHJ, mapped to the same chromosomal region (92E) as does D-Stat, had an incompletely penetrant pair rule phenotype, and exhibited aberrant expression of the pair rule gene even skipped (eve) at the cellular blastoderm stage. Two D-STAT-binding sites were identified within the eve stripe 3 enhancer region. Mutations in either of the STAT-binding sites greatly decreased the stripe 3 expression in transgenic flies. Clearly, the JAK-STAT pathway is connected to Drosophila early development.

The turnover of endoplasmic reticulum (ER) ensures the correct biological activity of its distinct domains. In mammalian cells, the ER is degraded via a selective autophagy pathway (ER-phagy), mediated by two specific receptors: FAM134B, responsible for the turnover of ER sheets and SEC62 that regulates ER recovery following stress. Here, we identified reticulon 3 (RTN3) as a specific receptor for the degradation of ER tubules. Oligomerization of the long isoform of RTN3 is sufficient to trigger fragmentation of ER tubules. The long N-terminal region of RTN3 contains several newly identified LC3-interacting regions (LIR). Binding to LC3s/GABARAPs is essential for the fragmentation of ER tubules and their delivery to lysosomes. RTN3-mediated ER-phagy requires conventional autophagy components, but is independent of FAM134B. None of the other reticulon family members have the ability to induce fragmentation of ER tubules during starvation. Therefore, we assign a unique function to RTN3 during autophagy.DOI: http://dx.doi.org/10.7554/eLife.25555.001