Disease relevance of BACE2

• As glia are 10 times more abundant in brain compared with neurons, our data indicate that BACE2 could indeed contribute to Abeta generation in the brains of Alzheimer disease and, in particular, Down syndrome patients [1].
• Overexpression of BACE2 by lentivirus markedly reduced Abeta production in primary neurons derived from Swedish mutant APP transgenic mice [2].
• We have produced mature BACE2 by expression of pro-BACE2 in Escherichia coli as inclusion bodies, followed by refolding and autocatalytic activation at pH 3 [3].
• Presence of BACE1 and BACE2 in muscle fibres of patients with sporadic inclusion-body myositis [4].
• A novel aspartic protease gene, ALP56, is up-regulated in human breast cancer independently from the cathepsin D gene [5].

Psychiatry related information on BACE2

• BACE2 could be involved in the Alzheimer-like neuropathology of Down syndrome, as well as in Alzheimer's disease linked to chromosome 21 but not showing mutations in APP [6].
• BACE2 appears to be associated with the early onset of dementia in patients with Down's syndrome, and it has been shown to be highly expressed in breast cancers [3].
• Findings from clinical and duplex ultrasound scan (DU) examinations were compared with the CEAP classification, its adjunctive venous clinical severity score, and sensory thresholds [7].

High impact information on BACE2

• The second cleavage is effected by Presenilin, an unusual polytopic aspartyl protease that apparently cleaves Notch and numerous other single-transmembrane substrates within the lipid bilayer [8].
• Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity [9].
• Our results indicate that the two transmembrane aspartate residues are critical for both presenilin-1 endoproteolysis and gamma-secretase activity, and suggest that presenilin 1 is either a unique diaspartyl cofactor for gamma-secretase or is itself gamma-secretase, an autoactivated intramembranous aspartyl protease [10].
• 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 [11].
• Presenilin itself appears to be a novel polytopic aspartyl protease of the GxGD type, whereas the other components might be required for substrate recognition, complex assembly, stability and targeting of the complex to its sites of action [12].

Chemical compound and disease context of BACE2

• The apolipoprotein E epsilon4 allele, oestrogen deficiency, high levels of Abeta1-42 peptide, elevated expression of BACE2, and valine polymorphism of prion protein gene are associated with earlier onset of dementia in DS individuals [13].
• gamma-Secretase is an intramembrane-cleaving aspartyl protease complex that mediates the final cleavage of beta-amyloid precursor protein to liberate the neurotoxic amyloid-beta peptide implicated in Alzheimer's disease [14].
• Aspartyl protease inhibitor pepstatin binds to the presenilins of Alzheimer's disease [15].
• ALP56 gene expression was dose-dependently down-regulated in T-47D breast cancer cells treated with estradiol, while cathepsin D was up-regulated [5].
• Human immunodeficiency virus 1 (HIV-1) protease is an aspartyl protease composed of two identical protomers linked by a four-stranded antiparallel beta-sheet consisting of the NH2- and COOH-terminal segments (Weber, I.T. (1990) J. Biol. Chem. 265, 10492-10496) [16].

Biological context of BACE2

• BACE and BACE2 respond identically to conservative beta-site mutations, and alteration of a common active site Arg inhibits beta-site cleavage but not cleavage within Abeta by both enzymes [17].
• However, a combined deficiency of BACE2 and BACE1 enhanced the bace1-/- lethality phenotype [1].
• We investigated the role of endogenous BACE2 in A beta production in cells by selective inactivation of its transcripts using RNA interference [18].
• We report the mRNA expression profile, DNA sequence, and molecular characterization of the BACE2 gene, located on chromosome 21q22 [19].
• On either side of the proximal promoter region, two negative regulatory domains might reduce BACE2 expression under an induced condition [19].

Anatomical context of BACE2

• 3. The BACE2 gene expresses more strongly in peripheral tissues, although BACE2 mRNA is found in the majority of brain regions, including the postcentral gyrus and temporal lobe [19].
• Our data argue against BACE2 being involved in the formation of neuritic plaques in AD [20].
• Asp1 colocalizes with APP in the Golgi/endoplasmic reticulum compartments of cultured cells [21].
• BACE2 localizes in the endoplasmic reticulum, Golgi, trans-Golgi network, endosomes, and plasma membrane, and its cellular localization patterns depend on the presence of its transmembrane domain [22].
• Northern analysis reveals that BACE2 mRNA is expressed at low levels in most human peripheral tissues and at higher levels in colon, kidney, pancreas, placenta, prostate, stomach, and trachea [23].

Associations of BACE2 with chemical compounds

• Mutation of one of the conserved catalytic aspartic acid residues in the active site of Asp1 to asparagine (D110N) abolished this cleavage [24].
• Asp1 cleaved a maltose-binding protein-Asp1 prodomain fusion protein and a synthetic peptide at this site [24].
• Solubilized gamma-secretase activity is inhibited by pepstatin and more potently by a novel aspartyl protease transition-state analog inhibitor that blocks formation of Abeta40 and Abeta42 in mammalian cells [25].
• An aspartyl protease has been suggested to cleave the NH2-terminal propeptide resulting in a 25-kDa intermediate [26].
• These compounds possess a hydroxyethylene dipeptide isostere of aspartyl protease transition state analogs, suggesting gamma-secretase may be an aspartyl protease [27].

Physical interactions of BACE2

• BACE2 is a membrane-bound aspartic protease of the A1 family with a high level of sequence homology to BACE1 [3].

Enzymatic interactions of BACE2

• Although memapsin 1 hydrolyzes the beta-secretase site of APP, it is not significantly present in the brain, and no direct evidence links it to Alzheimer's disease [28].
• ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site [21].

Regulatory relationships of BACE2

• This difficulty was confirmed by the finding that several potent memapsin 2 inhibitors effectively inhibited memapsin 1 as well [28].
• When full-length Asp1(D110N) was expressed in COS-7 cells, it was not processed, suggesting that no other proteinase can activate Asp1 in these cells [24].
• We conclude disruption of intramolecular hydrogen bonding between Thr18 and Asp21 enhances p53 transactivation by modulating Mdm-2 binding, facilitating TAF(II)31 recruitment [29].
• This plasma renin form would be expected to be activated in association with the recently described renin/prorenin aspartyl protease receptor and to participate in local pathophysiological processes [30].

Other interactions of BACE2

• These data suggest that BACE2 contributes to Abeta production in individuals bearing the Flemish mutation, and that selective inhibition of these highly similar proteases may be feasible and therapeutically advantageous [17].
• Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice [1].
• BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein [17].
• Here we describe the characterization of a second highly related aspartic proteinase, Asp1 as a second beta-secretase candidate [21].
• Aspartyl protease Cathepsin D (CTSD) has been suggested to play a role in the pathogenesis of sporadic Alzheimer's disease (AD) due to interference with protein degradation mechanisms [31].

Analytical, diagnostic and therapeutic context of BACE2

• Though Sp1 can regulate both BACE1 and BACE2 genes, comparative sequence analysis and transcription factor prediction showed little similarity between the two promoters [20].
• In addition, in situ hybridization of adult rat brain shows that BACE2 mRNA is expressed at very low levels in most brain regions [23].
• 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 [32].
• Western blot analysis revealed no difference between DS and control in BACE-2 protein levels in the intracellular compartment [33].
• The analysis revealed a 2.6-fold increase in BACE-2 mRNA levels in the DS group compared to the levels observed in the control group [33].

References