Disease relevance of BACE1

• Moreover, the levels of mature BACE1 were increased in human neuroblastoma cell line, SH-SY5Y, stably expressing wild-type PS1, compared to native cells [1].
• The protease domain of memapsin 2 cDNA was expressed in Escherichia coli and was purified [2].
• Presence of BACE1 and BACE2 in muscle fibres of patients with sporadic inclusion-body myositis [3].
• Additionally, in animal models of chronic gliosis and in brains of AD patients, there is BACE1 expression in reactive astrocytes [4].
• Thus by up-regulating of BACE1 mRNA and protein level in the neuronal cell, hypoxia may be a linkage in the pathophysiology between cerebravascular diseases and AD [5].
• BACE1 protein and activity levels are significantly increased in the brain of patients with Alzheimer's disease [6].

Psychiatry related information on BACE1

• BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease [7].
• Here we show that BACE1 null mice engineered to overexpress human APP (BACE1(-/-).Tg2576(+)) are rescued from Abeta-dependent hippocampal memory deficits [7].
• Highlights of the conference included reports on brain imaging, the discovery of mutations in the progranulin gene that cause frontotemporal dementia, the finding that neuregulin-1 is a substrate for BACE1 and new interest in the connection between Alzheimer's disease and metabolic syndromes [8].
• Endogenous beta2 processing and Na(v)1.1 protein levels are elevated in brains of BACE1-transgenic mice and Alzheimer's disease patients with high BACE1 levels [9].

High impact information on BACE1

• Our data support a mechanism by which reticulon proteins block access of BACE1 to amyloid precursor protein and reduce the cleavage of this protein [10].
• 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 [11].
• Memapsin 2 (beta-secretase) is a membrane-associated aspartic protease involved in the production of beta-amyloid peptide in Alzheimer's disease and is a major target for drug design [12].
• The active site of memapsin 2 is more open and less hydrophobic than that of other human aspartic proteases [12].
• Antisense inhibition of endogenous BACE messenger RNA decreased the amount of beta-secretase cleavage products, and purified BACE protein cleaved APP-derived substrates with the same sequence specificity as beta-secretase [13].

Chemical compound and disease context of BACE1

• Taken together, these data indicate that the lipid second messenger ceramide, which is elevated in the brains of Alzheimer's disease patients, increases the half-life of BACE1 and thereby promotes Abeta biogenesis [14].
• Here, we show that relatively little wild-type BACE is found in rafts prepared from a human neuroblastoma cell line (SH-SY5Y) by using Triton X-100 as detergent [15].
• Heparin activates beta-secretase (BACE1) of Alzheimer's disease and increases autocatalysis of the enzyme [16].
• Low nanomolar inhibition of BACE1, an enzyme implicated in the cascade of events leading to plaque formation in Alzheimer's disease, was found with a pyrrolidinone analogue [17].
• Alzheimer's beta-secretase (BACE1), an aspartic protease, cleaves amyloid precursor protein to produce a neurotoxic peptide, amyloid-beta, which plays a role in triggering Alzheimer's disease [18].

Biological context of BACE1

• BACE1 gene expression is controlled by a TATA-less promoter [19].
• Selective inactivation of BACE1 by RNA interference results in decreased beta-cleaved secreted APP and A beta peptide secretion from cells, as expected [20].
• We report here that BACE1 mice display a complex phenotype [21].
• The highest expressing BACE1 transgenic line was mated to transgenic mice containing human APP transgenes [22].
• Therefore, the present study investigates the effect of this M2 muscarinic receptor down-regulation by siRNA on total gene expression and on regulation of BACE1 in particular in SK-SH-SY5Y cells [23].

Anatomical context of BACE1

• Endogenous HS immunoprecipitates with BACE1 and colocalizes with BACE1 in the Golgi complex and at the cell surface, two of its putative sites of action [24].
• Our studies demonstrate that BACE1 and BACE2 (a) are expressed in normal adult muscle at the postsynaptic domain of neuromuscular junctions, and in cultured human muscle; (b) are accumulated in the form of plaque-like inclusions in both s-IBM and h-IBM vacuolated muscle fibers; and (c) are immunoreactive in necrotizing muscle fibers [25].
• We show that the levels of exogenous and endogenous mature BACE1 expressed in presenilin-deficient mouse embryonic fibroblasts (PS-/-MEFs) were reduced significantly compared to those in wild-type MEFs [1].
• In transfected cells both BACE1A, which encodes the originally described full-length BACE1 protein and the close homolog BACE2 localized mainly to post-Golgi membranes [26].
• Here, we demonstrate that BACE1 binds to nicastrin, a component of gamma-secretase complexes, in vitro, and that nicastrin activates beta-secretase activity in COS-7 cells [27].

Associations of BACE1 with chemical compounds

• We show that HS and heparin interact directly with BACE1 and inhibit in vitro processing of peptide and APP substrates [24].
• Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's beta-secretase [24].
• Pulse-chase and time-course degradation experiments showed that ceramide post-translationally stabilizes the beta-secretase BACE1 [14].
• While PB2-T1 shares similar substrate specificities with BACE1 and other 'general' aspartic proteases, the specificity of PB2-T2 is more constrained, apparently preferring to cleave at the NH2-terminal side of paired basic residues [28].
• The BACE1 protein level was increased in a time- and dosage-dependent manner in the inducible BACE1 stable cells by treatment with inducer ponasterone A [29].
• We used an alternate strategy to explore the function of BACE1 in membrane microdomains without altering the cellular cholesterol level [30].

Physical interactions of BACE1

• Elevated BACE1 expression coupled with increased deposition provides functional evidence for beta-secretase as a primary effector in regional amyloid deposition in the AD brain [22].
• BACE1 interacts with nicastrin [27].
• Thus, functional and gel shift analysis indicate that the 91 bp fragment containing the AP2 and SP1 binding sites constitutes the core promoter region of BACE [31].
• Here we show that reticulon family members are binding partners of BACE1 [10].
• Comparative modeling of the three-dimensional structure of BACE in complex with its substrate shows that several residues confer specificity of the enzyme for APP [32].

Enzymatic interactions of BACE1

• Recombinant memapsin 2 specifically hydrolyzed peptides derived from the beta-secretase site of both the wild-type and Swedish mutant beta-amyloid precursor protein (APP) with over 60-fold increase of catalytic efficiency for the latter [2].
• Recombinant memapsin 2 also cleaved a peptide derived from the processing site of presenilin 1, albeit with poor kinetic efficiency [2].
• The amyloid precursor protein is cleaved within its ectodomain by beta-amyloid-converting enzyme (BACE) yielding C99, which is further cleaved by gamma-secretase within its putative transmembrane domain (TMD) [33].
• Recent reports show that furin cleaves the pro-peptide of ASP-2, whereas ASP-1 undergoes auto-catalysis [34].
• We found that BACE1 cleaved polysialyltransferase ST8Sia IV (PST) in vitro [35].

Co-localisations of BACE1

• Human BACE forms dimers and colocalizes with APP [36].

Regulatory relationships of BACE1

• This difficulty was confirmed by the finding that several potent memapsin 2 inhibitors effectively inhibited memapsin 1 as well [37].
• Our findings identify HS as a natural regulator of BACE1 and suggest a novel mechanism for control of APP processing [24].
• Novel mutations introduced at the beta-site of amyloid beta protein precursor enhance the production of amyloid beta peptide by BACE1 in vitro and in cells [38].
• Here, we show that GGA1 regulates the retrograde transport of internalized BACE1 from endosomal compartments to the TGN by direct interaction in a phosphorylation-dependent manner [39].
• Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates the transcription of BACE1 as well as inflammatory responses in the brain and atherosclerotic risk factors known to be involved also in AD [40].

Other interactions of BACE1

• These and other results suggest that memapsin 2 fits all of the criteria of beta-secretase, which catalyzes the rate-limiting step of the in vivo production of the beta-amyloid (Abeta) peptide leading to the progression of Alzheimer's disease [2].
• Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice [21].
• A crystal structure of the complex between memapsin 2 phosphoserine peptide and GGA1 VHS was solved at 2.6 A resolution [41].
• These observations suggest that the endocytosis and intracellular transport of memapsin 2, mediated by its cytosolic domain, may involve the binding of GGA1 and GGA2 [42].
• However,when we combined our results with those previously reported, a clear increase of the risk to develop AD appeared in subjects carrying both the BACE1 exon 5 GG genotype and the APOE epsilon4-allele (crude OR = 2.2, P = 0.004) [43].

Analytical, diagnostic and therapeutic context of BACE1

• We now report that the C-terminal domain of PAR-4 is necessary for forming a complex with the cytosolic tail of BACE1 in co-immunoprecipitation assays and in vitro pull-down experiments [44].
• A wide variety of BACE1 inhibitors have been reported, several of which have demonstrated highly promising efficacy in animal models of AD [45].
• To investigate whether BACE1 and BACE2 play a role in normal and diseased human muscle, we have now studied them by immunocytochemistry and immunoblotting in 35 human muscle biopsies, including: 5 s-IBM; 5 chromosome-9p1-linked quadriceps-sparing h-IBM; and 25 control muscle biopsies [25].
• Using these antibodies, BACE1 was characterized in temporal lobe cortices by Western blotting and immunohistochemistry [46].
• Four hours after treatment, we observed that reduced energy production caused a approximately 150% increase of cerebral BACE1 levels compared with control [47].

References