Sequence 254 (BACE1-4 , BACE14)

Sequence BACE1-4 , BACE14
Target	BACE1 ( Homo sapiens / Mus musculus )
Description	Beta-site APP-cleaving enzyme 1 Ensembl: ENSG00000186318 UniGene: Hs.504003 EntrezGene: 23621 Ensembl Chr11: 116661627 - 116692182 Strand: -1 GO terms: 0004190 0004194 0005768 0005794 0005887 0006508 0006509 0008233 0008798 0009049 0016020 0030424 0031410 0050435
Design	siRNA
Chemistry	RNA
Sequence	siRNA sense (21b) TTGGCTTTGCTGTCAGCGCNN / siRNA antisense (21b) GCGCTGACAGCAAAGCCAANN
Application	gene silencing
Name	BACE1-4 , BACE14

References

BACE1 suppression by RNA interference in primary cortical neurons.Kao SC, Krichevsky AM, Kosik KS, Tsai LH.J Biol Chem. 2004 Jan 16;279(3) :1942-9. Epub 2003 Nov 3.

Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Hache M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S, Bishop KM. J Child Neurol. 2016 Jun;31(7):899-906. PubMed:26823478

Background

Gene Function. Vassar et al. (1999) found that transient overexpression of BACE did not affect APP expression, but decreased alpha-secretase cleavage and increased beta-secretase activity in cells expressing wildtype or Swedish mutant (104760.0008) APP. BACE overexpression induced cleavage only at the known beta-secretase positions, asp1 and glu11. Vassar et al. (1999) concluded that their data provided strong evidence that the BACE aspartic protease is the long-sought APP beta-secretase.

From pharmacologic data, Yan et al. (1999) deduced that ASP2 has aspartyl-protease-like characteristics--acidic pH requirements and a signature sequence (asp--ser/thr--gly) found in most aspartyl enzymes (De Strooper and Konig, 1999). They demonstrated that solubilized ASP2 protein cleaved a synthetic APP peptide substrate at the beta-secretase site.

Sinha et al. (1999) described a membrane-bound enzyme activity for BACE that cleaved full-length APP at the beta-secretase cleavage site, and found it to be the predominant beta-cleavage activity in human brain.

Hussain et al. (1999) showed that point mutations in BACE at both of its active sites (asp--ser/thr--gly sequence) resulted in a protein that could no longer process APP to amyloid-beta.

Haniu et al. (2000) used immunoprecipitation, SDS-PAGE, and mass spectrometry analysis to show that BACE is a 70-kD integral membrane protein that is stable once it is constitutively glycosylated in the Golgi apparatus. Sequence and mass spectrometry analyses showed that asn153, asn172, asn223, and asn354 of the BACE ectodomain are N-glycosylation sites. In addition, the ectodomain contains 6 cys residues that form disulfide bridges between positions 216 and 420, 278 and 443, and 330 and 380. Haniu et al. (2000) concluded that the presence of the transmembrane domain and the unusual disulfide structures make BACE, a prime target for AD treatment, an atypical pepsin family member. Animal Model.Luo et al. (2001) found that mice deficient in Bace1 are healthy, fertile, and appear normal in gross anatomy, tissue histology, hematology, and clinical chemistry. Bace1 -/- mice who are also hemizygous for an amyloid precursor protein transgene lack brain beta-amyloid and beta-secretase-cleaved APP C-terminal fragments. These results provided validation of BACE1 as the major beta-secretase in vivo and suggested that therapeutic inhibition of BACE1 for the treatment of Alzheimer disease may be free of mechanism-based toxicity.

Roberds et al. (2001) generated 2 lines of BACE knockout mice and characterized them for pathology, beta-secretase activity, and amyloid-beta production. The mice appeared to develop normally and showed no consistent phenotypic differences from their wildtype littermates, including overall normal tissue morphology and brain histochemistry, normal blood and urine chemistries, normal blood-cell composition, and no overt behavioral and neuromuscular effects. Brain and primary cortical cultures from BACE knockout mice showed no detectable beta-secretase activity, and primary cortical cultures from BACE knockout mice produced much less amyloid-beta from APP. The authors proposed that BACE may be a specific therapeutic target for treatment of AD.

Ohno et al. (2004) generated bigenic BACE knockout mice overexpressing a mutant APP protein (Tg2576). Compared to Tg2576 mice, the bigenic BACE -/-*Tg2576+ mice performed significantly better on hippocampus-dependent learning and recognition and were rescued to wildtype performance. The bigenic mice had increased hippocampal neuronal cholinergic stimulation compared to the Tg2576 mice. The behavioral and electrophysiologic rescue of deficits in the bigenic mice correlated with a dramatic reduction of cerebral amyloid-beta-40 and amyloid-beta-42 levels, and occurred before amyloid deposition in the Tg2576 mice. Ohno et al. (2004) concluded that lower beta-amyloid levels are beneficial for AD-associated memory impairments and suggested BACE as a therapeutic target.

Contrary to earlier findings, Dominguez et al. (2005) found that Bace1-null mice displayed a complex phenotype, including loss of about 19% of null pups within the first 3 to 6 days of birth. Of those remaining, 24% showed growth retardation and died by 3 to 4 weeks of age from a wasting syndrome. Bace1-null mice surviving to adulthood were fertile and showed no histologic or anatomic abnormality. Bace1-null mice were hyperactive compared with control littermates, and electrophysiologic recording of Bace1-deficient neurons revealed a rightward shift in the steady-state inactivation curve of voltage-gated sodium channels. Bace1 deficiency resulted in an almost complete block of amyloid-beta generation in neurons, but not in glial cells, where the beta-secretase activity was associated with Bace2. In contrast to Bace1-null mice, Bace2-null mice appeared normal. However, deletion of both Bace1 and Bace2 enhanced the postnatal lethal phenotype associated with Bace1 deletion.

Ma et al. (2007) showed that the Tg5469 transgenic mouse strain overexpressing human APP did not develop AD pathology or memory deficits, but instead showed enhanced spatial memory. Studies on long-term potentiation demonstrated that enhanced synaptic activity in the hippocampus was a dynamic process dependent on prior synaptic activity and was correlated with increased levels of APP intracellular fragments (AICD), but not with other APP cleavage products. Ablation of 1 or both copies of the Bace1 gene in Tg5469 mice decreased the enhanced spatial memory and resulted in a decrease of AICD, but not of other APP cleavage products. Ma et al. (2007) concluded that physiologic BACE1-mediated cleavage of APP can facilitate learning, memory, and synaptic plasticity, perhaps via AICD.