Beta-secretase 1

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BACE inhibitor
)
BACE1
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000186318

ENSMUSG00000032086

UniProt

P56817

P56818

RefSeq (mRNA)

NM_001145947
NM_011792

RefSeq (protein)

NP_001139419
NP_035922

Location (UCSC)Chr 11: 117.29 – 117.32 MbChr 9: 45.75 – 45.78 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the BACE1 gene.[5] Expression of BACE1 is observed mainly in neurons.

BACE1 is an

palmitoylated.[citation needed
]

The BACE1 expression is influenced by the inflammatory state: during AD the cytokines reduce the PPAR1 an inhibitor of BACE1 mRNA.[citation needed]

Role in Alzheimer's disease

Processing of the amyloid precursor protein

BACE1 is the major beta secretase for the generation of

peptides in the neurons.[8]

Generation of the 40 or 42

gamma-secretase cleaves APP closer to the cell membrane than BACE1 does, it removes a fragment of the amyloid-β peptide. Initial cleavage of APP by α-secretase rather than BACE1 prevents eventual generation of amyloid-β, forming P3, this demonstrates that BACE1 and Alpha secretase
compete for the APP processing.

Unlike APP and the

BACE2 is a close homolog
of BACE1 with no reported APP cleavage in vivo.

The physiological purpose of BACE's cleavage of APP and other transmembrane proteins is unknown: some studies observed that BACE1 is involved in

myelination (it is co-express with neuregulin 1 type III). In a manner analogous to APP processing, the VGSC subunit beta is a substrate for BACE1.[9]

However a single residue mutation in APP reduces the ability of BACE1 to cleave it to produce amyloid-beta and reduces the risk of Alzheimer's disease and other cognitive declines.[10][11]

BACE inhibitors

Drugs to block this enzyme (BACE inhibitors) in theory would prevent the buildup of beta-amyloid and (per the

Amyloid hypothesis) may help slow or stop Alzheimer's disease.[12]

For Alzheimer's disease

Several companies are in the early stages of development and testing of this potential class of treatment.[13][14] In March 2008 phase I results were reported for CoMentis Inc's candidate CTS-21166.[15]

In April 2012 Merck & Co., Inc reported phase I results for its candidate verubecestat (MK-8931).[16] Merck began a Phase II/III trial of MK-8931 in December, 2012 estimated to be completed in July 2019.[17] In February 2017, Merck halted its late-stage trial of verubecestat for mild to moderate Alzheimer's disease after it was reported as having "virtually no chance" of working according to an independent panel of experts. This came just three months after Eli Lilly & Co. announced its own setback with solanezumab.

In September 2014 AstraZeneca and Eli Lilly and Company announced an agreement to codevelop lanabecestat (AZD3293).[18] A pivotal Phase II/III clinical trial of lanabecestat started in late 2014,[19] but was halted in 2018 before its planned conclusion due to poor results.[20]

Another BACE1 inhibitor that has reached phase II trials is the Eli Lilly's inhibitor LY2886721. The data on phase I trial were first presented at the Alzheimer's Association International conference in 2012. Daily dosing during 2 weeks, reduced BACE1 activity by 50–75% and CSF Aβ42 by 72% (Willis et al., 2012; Bowman Rogers and Strobel, 2013). Recently, Lilly reported that the phase II trial of LY2886721 was terminated due to liver abnormalities that were found in 4 out of 45 patients (Rogers, 2013). This toxicity, however, does not have to be related to the working mechanism of the inhibitor, but can represent off-target effects as the livers of BACE1 knockout mice are normal.

Potential side effects

Tests in mice have indicated that BACE proteases, specifically BACE1, are necessary for the proper function of muscle spindles.[21] These results raise the possibility that BACE inhibiting drugs currently being investigated for the treatment of Alzheimer's may have significant side effects related to impaired motor coordination,[22] though BACE1 knockout mice are healthy.[23]

Relationship to plasmepsin

BACE1 is distantly related to the pathogenic aspartic-acid protease plasmepsin, which is a potential target for future anti-malarial drugs.[24]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000186318 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032086 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. S2CID 42481897
    .
  6. S2CID 8432207
    .
  7. PMID 10801872
    .
  8. S2CID 11973104
    .
  9. PMID 17576410
    .
  10. ^ "Alzheimer's-fighting gene may inspire treatments". July 2012.
  11. S2CID 4333449
    .
  12. PMID 31595293
    .
  13. PMID 16644763
    .
  14. PMID 17685503
    .
  15. ^ "CoMentis BACE Inhibitor Debuts". April 2008.
  16. ^ "Merck Presents Results of a Phase I Clinical Trial Evaluating Investigational BACE inhibitor MK-8931 at American Academy of Neurology". April 2012. Archived from the original on 2012-07-28.
  17. ^ "Merck Initiates Phase II/III Study of Investigational BACE Inhibitor, MK-8931, for Treatment of Alzheimer's Disease". December 2012. Archived from the original on 2017-02-27. Retrieved 2012-12-13.
  18. ^ "AstraZeneca and Lilly announce alliance to develop and commercialise BACE inhibitor AZD3293 for Alzheimer's disease". 16 Sep 2014. Retrieved 8 Oct 2014.
  19. ^ "AstraZeneca and Lilly move Alzheimer's drug into big trial". Reuters. December 2014. Archived from the original on 2015-10-25. Retrieved 2017-06-30.
  20. ^ "Update on Phase III Clinical Trials of lanabecestat". 12 June 2018. Retrieved 20 June 2018.
  21. PMID 23792428
    .
  22. S2CID 36382718
    .
  23. PMID 11406613
    .
  24. PMID 20130644
    .

Further reading

External links
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