Beta-secretase 1

Last updated
BACE1
Protein BACE1 PDB 1fkn.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases BACE1 , ASP2, BACE, HSPC104, beta-secretase 1
External IDs OMIM: 604252 MGI: 1346542 HomoloGene: 8014 GeneCards: BACE1
EC number 3.4.23.46
Orthologs
SpeciesHumanMouse
Entrez

23621

23821

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 Mb Chr 9: 45.75 – 45.78 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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 aspartic acid protease important in the formation of myelin sheaths in peripheral nerve cells: in mice the expression of BACE1 is high in the postnatal stages, when myelination occurs. [6] The transmembrane protein contains two active site aspartate residues in its extracellular protein domain and may function as a dimer, its cytoplasmic tail is required for the correct maturation and an efficient intracellular trafficking, but does not affect the activity. It is produced as a pro-enzyme, the endoproteolitc removal occurs after BACE leaves endoplasmic reticulum, in the Golgi apparatus. In addition the pro-peptide receives additional sugars to increase the molecular mass. [7] and the tail became a 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 APP processing.png
Processing of the amyloid precursor protein

BACE1 is the major beta secretase for the generation of amyloid-β peptides in the neurons. [8]

Generation of the 40 or 42 amino acid-long amyloid-β peptides that aggregate in the brain of Alzheimer's patients requires two sequential cleavages of the amyloid precursor protein (APP). Extracellular cleavage of APP by BACE1 creates a soluble extracellular fragment and a cell membrane-bound fragment referred to as C99. Cleavage of C99 within its transmembrane domain by γ-secretase releases the intracellular domain of APP and produces amyloid-β. Since 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 presenilin proteins important in γ-secretase, no known mutations in the gene encoding BACE1 cause early-onset, familial Alzheimer's disease, which is a rare form of the disorder. However, levels of this enzyme have been shown to be elevated in the far more common late-onset sporadic Alzheimer's. 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]

Related Research Articles

<span class="mw-page-title-main">Beta-secretase 2</span> Enzyme found in humans

Beta-secretase 2 is an enzyme that cleaves Glu-Val-Asn-Leu!Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein. BACE2 is a close homolog of BACE1.

<span class="mw-page-title-main">Cathepsin</span> Family of proteases

Cathepsins are proteases found in all animals as well as other organisms. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave. Most of the members become activated at the low pH found in lysosomes. Thus, the activity of this family lies almost entirely within those organelles. There are, however, exceptions such as cathepsin K, which works extracellularly after secretion by osteoclasts in bone resorption. Cathepsins have a vital role in mammalian cellular turnover.

<span class="mw-page-title-main">Amyloid beta</span> Group of peptides

Amyloid beta denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

<span class="mw-page-title-main">Amyloid-beta precursor protein</span> Mammalian protein found in humans

Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene APP and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.

<span class="mw-page-title-main">Amyloid-beta precursor protein secretase</span>

Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane.

<span class="mw-page-title-main">Gamma secretase</span> Type of protein

Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 37-43 amino acid peptide called amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch, ErbB4, E-cadherin, N-cadherin, ephrin-B2, or CD44.

<span class="mw-page-title-main">Presenilin</span>

Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's disease by Peter St George-Hyslop. Vertebrates have two presenilin genes, called PSEN1 that codes for presenilin 1 (PS-1) and PSEN2 that codes for presenilin 2 (PS-2). Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1.

<span class="mw-page-title-main">Alpha secretase</span> Family of proteolytic enzymes

Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein (APP) in its transmembrane region. Specifically, alpha secretases cleave within the fragment that gives rise to the Alzheimer's disease-associated peptide amyloid beta when APP is instead processed by beta secretase and gamma secretase. The alpha-secretase pathway is the predominant APP processing pathway. Thus, alpha-secretase cleavage precludes amyloid beta formation and is considered to be part of the non-amyloidogenic pathway in APP processing. Alpha secretases are members of the ADAM family, which are expressed on the surfaces of cells and anchored in the cell membrane. Several such proteins, notably ADAM10, have been identified as possessing alpha-secretase activity. Upon cleavage by alpha secretases, APP releases its extracellular domain - a fragment known as APPsα - into the extracellular environment in a process known as ectodomain shedding.

<span class="mw-page-title-main">Insulin-degrading enzyme</span> Mammalian protein found in Homo sapiens

Insulin-degrading enzyme, also known as IDE, is an enzyme.

<span class="mw-page-title-main">Presenilin-1</span> Protein-coding gene in the species Homo sapiens

Presenilin-1(PS-1) is a presenilin protein that in humans is encoded by the PSEN1 gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.

<span class="mw-page-title-main">ADAM10</span> Protein-coding gene in the species Homo sapiens

A Disintegrin and metalloproteinase domain-containing protein 10, also known as ADAM10 or CDw156 or CD156c is a protein that in humans is encoded by the ADAM10 gene.

<span class="mw-page-title-main">Semagacestat</span> Chemical compound

Semagacestat (LY-450139) was a candidate drug for a causal therapy against Alzheimer's disease. It was originally developed by Eli Lilly and Elan, and clinical trials were conducted by Eli Lilly. Phase III trials included over 3000 patients, but in August 2010, a disappointing interim analysis, in which semagacestat performed worse than the placebo, led to the trials being stopped.

<span class="mw-page-title-main">Early-onset Alzheimer's disease</span> Alzheimers disease developed before the age of 65

Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer's and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.

<span class="mw-page-title-main">Protein pigeon homolog</span> Protein-coding gene in the species Homo sapiens

Protein pigeon homolog also known as gamma-secretase activating protein (GSAP) is a protein that in humans is encoded by the PION gene.

The Alzheimer's disease biomarkers are neurochemical indicators used to assess the risk or presence of the disease. The biomarkers can be used to diagnose Alzheimer's disease (AD) in a very early stage, but they also provide objective and reliable measures of disease progress. It is imperative to diagnose AD disease as soon as possible, because neuropathologic changes of AD precede the symptoms by years. It is well known that amyloid beta (Aβ) is a good indicator of AD disease, which has facilitated doctors to accurately pre-diagnose cases of AD. When Aβ peptide is released by proteolytic cleavage of amyloid-beta precursor protein, some Aβ peptides that are solubilized are detected in CSF and blood plasma which makes AB peptides a promising candidate for biological markers. It has been shown that the amyloid beta biomarker shows 80% or above sensitivity and specificity, in distinguishing AD from dementia. It is believed that amyloid beta as a biomarker will provide a future for diagnosis of AD and eventually treatment of AD.

Intramembrane proteases (IMPs), also known as intramembrane-cleaving proteases (I-CLiPs), are enzymes that have the property of cleaving transmembrane domains of integral membrane proteins. All known intramembrane proteases are themselves integral membrane proteins with multiple transmembrane domains, and they have their active sites buried within the lipid bilayer of cellular membranes. Intramembrane proteases are responsible for proteolytic cleavage in the cell signaling process known as regulated intramembrane proteolysis (RIP).

<span class="mw-page-title-main">P3 peptide</span>

p3 peptide also known as amyloid β- peptide (Aβ)17–40/42 is the peptide resulting from the α- and γ-secretase cleavage from the amyloid precursor protein (APP). It is known to be the major constituent of diffuse plaques observed in Alzheimer's disease (AD) brains and pre-amyloid plaques in people affected by Down syndrome. However, p3 peptide's role in these diseases is not truly known yet.

<span class="mw-page-title-main">Blarcamesine</span> Medication

Blarcamesine is an experimental drug developed by Anavex Life Sciences.

<span class="mw-page-title-main">Verubecestat</span> Chemical compound

Verubecestat (MK-8931) was an experimental drug for the treatment of Alzheimer's disease. It is an inhibitor of beta-secretase 1 (BACE1), which, after initial promise proved disappointing.

<span class="mw-page-title-main">Buntanetap</span> Chemical compound

Buntanetap is an orally-administered small molecule inhibitor of several neurotoxic proteins that is under investigation in the treatment of Alzheimer's disease, frontotemporal dementia, chronic traumatic encephalopathy and Parkinson's disease. It is the (+) enantiomer of phenserine, as the (-) enantiomer also has unwanted anticholinergic effects. It is currently in phase III trials for the treatment of Parkinson's.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000186318 - Ensembl, May 2017
  2. 1 2 3 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. ↑ Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (Oct 1999). "Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE". Science. 286 (5440): 735–41. doi:10.1126/science.286.5440.735. PMID   10531052. S2CID   42481897.
  6. ↑ Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C (Oct 2006). "Control of peripheral nerve myelination by the beta-secretase BACE1". Science. 314 (5799): 664–6. Bibcode:2006Sci...314..664W. doi:10.1126/science.1132341. PMID   16990514. S2CID   8432207.
  7. ↑ Capell A, Steiner H, Willem M, Kaiser H, Meyer C, Walter J, Lammich S, Multhaup G, Haass C (2000-10-06). "Maturation and Pro-peptide Cleavage of β-Secretase". Journal of Biological Chemistry. 275 (40): 30849–30854. doi: 10.1074/jbc.M003202200 . ISSN   0021-9258. PMID   10801872.
  8. ↑ Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC (March 2001). "BACE1 is the major β-secretase for generation of Aβ peptides by neurons". Nature Neuroscience. 4 (3): 233–234. doi:10.1038/85064. ISSN   1546-1726. PMID   11224536. S2CID   11973104.
  9. ↑ Kim DY, Carey BW, Wang H, Ingano LA, Binshtok AM, Wertz MH, Pettingell WH, He P, Lee VM, Woolf CJ, Kovacs DM (July 2007). "BACE1 regulates voltage-gated sodium channels and neuronal activity". Nature Cell Biology. 9 (7): 755–764. doi:10.1038/ncb1602. ISSN   1465-7392. PMC   2747787 . PMID   17576410.
  10. ↑ "Alzheimer's-fighting gene may inspire treatments". July 2012.
  11. ↑ Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jönsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K (Aug 2012). "A mutation in APP protects against Alzheimer's disease and age-related cognitive decline". Nature. 488 (7409): 96–9. Bibcode:2012Natur.488...96J. doi:10.1038/nature11283. PMID   22801501. S2CID   4333449.
  12. ↑ Pradeepkiran JA, Reddy AP, Yin X, Manczak M, Reddy PH (2020). "Protective Effects of BACE1 Inhibitory Ligand Molecules Against Amyloid Beta-Induced Synaptic and Mitochondrial Toxicities in Alzheimer's Disease". Human Molecular Genetics. 29 (1): 49–69. doi:10.1093/hmg/ddz227. PMC   7001603 . PMID   31595293.
  13. ↑ Walker LC, Rosen RF (Jul 2006). "Alzheimer therapeutics-what after the cholinesterase inhibitors?". Age and Ageing. 35 (4): 332–5. doi:10.1093/ageing/afl009. PMID   16644763.
  14. ↑ Baxter EW, Conway KA, Kennis L, Bischoff F, Mercken MH, Winter HL, Reynolds CH, Tounge BA, Luo C, Scott MK, Huang Y, Braeken M, Pieters SM, Berthelot DJ, Masure S, Bruinzeel WD, Jordan AD, Parker MH, Boyd RE, Qu J, Alexander RS, Brenneman DE, Reitz AB (Sep 2007). "2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead". Journal of Medicinal Chemistry. 50 (18): 4261–4. doi:10.1021/jm0705408. 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. ↑ Cheret C, Michael Willem, Florence R Fricker, Hagen Wende (June 2013). "Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles". EMBO Journal. 32 (14): 2015–28. doi:10.1038/emboj.2013.146. PMC   3715864 . PMID   23792428.
  22. ↑ Pettersson A, Olsson E, Wahlund L (2005). "Motor Function in Subjects with Mild Cognitive Impairment and Early Alzheimer's Disease". Dementia and Geriatric Cognitive Disorders. 19 (5–6): 299–304. doi:10.1159/000084555. ISSN   1420-8008. PMID   15785030. S2CID   36382718.
  23. ↑ Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, Johnson-Wood K, Kappenman KE, Kawabe TT, Kola I, Kuehn R, Lee M, Liu W, Motter R, Nichols NF, Power M, Robertson DW, Schenk D, Schoor M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L (Jun 2001). "BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics". Human Molecular Genetics. 10 (12): 1317–24. doi: 10.1093/hmg/10.12.1317 . PMID   11406613.
  24. ↑ Russo I, Babbitt S, Muralidharan V, Butler T, Oksman A, Goldberg DE (Feb 2010). "Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte". Nature. 463 (7281): 632–6. Bibcode:2010Natur.463..632R. doi:10.1038/nature08726. PMC   2826791 . PMID   20130644.

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